1, 3-benzothiazinone derivatives and use thereof

ABSTRACT

This invention provides a compound represented by the formula (I):  
                 
 
wherein R 1  is a hydrogen atom, a halogen atom, hydroxy, nitro, optionally halogenated alkyl, alkoxy optionally having substituents, acyl or amino optionally having substituents; 
     R 2  is pyridyl, furyl, thienyl, pyrrolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, tetrahydroquinolyl or thiazolyl, each of which may have substituents; n is 1 or 2; or a salt. And this invention provides a safe pharmaceutical comprising the compound of the formula (I), which has an excellent apoptosis inhibitory effect and MIF binding effect, for preventing and/or treating heart disease, nervous degenerative disease, cerebrovascular disease, central nervous infectious disease, traumatorathy, demyelinating disease, bone and articular disease, kidney disease, liver disease, osteomyelodysplasia, AIDS, cancer, and the like.

TECHNICAL FIELD

This invention relates to 1,3-benzothiazinone derivatives, theproduction thereof and the use thereof, which are useful as drugs.

BACKGROUND ART

Apoptosis is closely involved in morphogenesis and histogenesis in thedevelopment process, maintenance of homeostasis, and bio-defense, and itis cell death having an important role in maintaining individual lives.When the death process regulated by genes is congenitally or postnatallyhindered, apoptosis is excessively induced or inhibited to causefunctional disorders in various organs, and thus diseases (SaishinIgaku, vol. 54, p. 825, 1999).

Lately, it has been come out that apoptosis plays an important role inoccurrence or development of several diseases (The New England Journalof Medicine, vol. 341, p. 759, 1999). In a mammalian heart, it isconsidered that heart muscle cells are finally differentiated cells, andlose proliferation activity. Accordingly, when heart muscle cellsdisappear by apoptosis, the heart contraction should be maintained onlyby remaining cells. Disappearance of heart muscle cells beyond thresholdnecessary for maintaining the heart contraction would result in abnormalheart functions and diseases. Apoptosis of heart muscle cells isactually observed in various animal models with cardiac insufficiency orin human patients with cardiac insufficiency, and it is noted thatdisappearance or lack of heart muscle cells by apoptosis may be involvedin onset and progress of cardiac insufficiency (The New England Journalof Medicine, vol. 335, p. 1182, 1996). It is further recognized that inheart muscle cells of human patients with cardiac insufficiency, anapoptosis-inhibitory factor Bcl-2 is expressed in excess, which is apossible compensation mechanism for cardiac insufficiency (The NewEngland Journal of Medicine, vol. 336, p. 1131, 1997); that serum levelsof soluble Fas (sFas has an inhibitory activity on apoptosis) whichlacks a membrane penetration domain in the Fas receptor known as anapoptosis inducing receptor, are increased significantly in proportionto severeness in NYHA class (New York Heart Association FunctionalClass) but independently of fundamental diseases, and thus an increasein serum levels of sFas is considered to be a compensatory mechanism toinhibit promotion of apoptosis in cardiac insufficiency (Journal of theAmerican College of Cardiology, vol. 29, p. 1214, 1997); and that in theheart with congestive cardiomyopathy, deoxyribonuclease I (DNase I)considered as a indicator of apoptosis is increased 7-fold or more thanin healthy persons (Journal of Molecular & Cell Cardiology, vol. 28, p.95, 1996).

When considered at the level of internal organs, the functions of theheart muscle are lowered in human cardiac diseases, and insufficientheart muscle contraction often endangers the maintenance of the life.Abnormalities, for example, myocardial disorders, abnormal heartpumping, pressure burden due to high blood pressure, volume burden dueto acute nephritis, and insufficient blood pumping caused by theseabnormalities lead to the onset of cardiac insufficiency. Against theseabnormalities, the sympathetic nervous system, the internal secretionsystem, and the like work together to start a compensating mechanism,resulting in cardiac hypertrophy accompanied by hypertrophy ofmyocardial cells. However, when these abnormalities occur alone or incombination persistently and chronically, the hypertrophied myocardialcells are not sufficiently supplied with blood, and thus the myocardialcells disappear due to apoptosis, etc. As a result, the compensatingmechanism fails to work, leading to a cardiac insufficiency syndromeaccompanied by myocardial disorders such as insufficient heartcontraction, a reduction in pumped blood, circulatory disorders ininternal organs, venostasis, and body fluid retention.

At present, the cardiac insufficiency syndrome is treated by usingcardiotonic glycosides such as digoxin, sympathetic agents such asdobutamine, phosphodiesterase inhibitors such as amrinone, vasodilatorssuch as hydralazine, calcium antagonist, angiotensin converting enzymeinhibitor and angiotensin receptor antagonist, and dilatedcardiomyopathy is treated by β-blockers, etc.

On the other hand, 1,3-benzothiazinone compound whose 2-position issubstituted by pyridyl is described in Chemical Abstract 51:17927g,however, the activity thereof is not described on it.

Furthermore, 1,3-benzothiazinone compound having heart muscle cellsapoptosis inhibitory effect are disclosed on WO 02/18356, which is anearlier application of this applicant.

The drugs for treating cardiac insufficiency syndrome don't possessefficient effect. Therefore the excellent drug for preventing and/ortreating cardiac insufficiency syndrome is desired.

DISCLOSURE OF THE INVENTION

The inventors assumed that inhibiting heart muscle cells apoptosis isuseful for preventing and treating cardiac insufficiency syndrome andexamined several ways. After that they produced a compound representedby the formula:

wherein R¹ is a hydrogen atom, a halogen atom, hydroxy, nitro,optionally halogenated alkyl, alkoxy optionally having substituents,acyl or amino optionally having substituents;

-   R² is pyridyl, furyl, thienyl, pyrrolyl, quinolyl, pyrazinyl,    pyrimidinyl, pyridazinyl, indolyl, tetrahydroquinolyl or thiazolyl,    each of which may have substituents;-   n is 1 or 2; or a salt thereof (hereinafter sometimes abbreviated as    Compound (I)); whose character is having pyridyl, furyl, thienyl,    pyrrolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl or indolyl,    each of which may have substituents, on 2-position of    1,3-benzothiazinone skeleton for the first time. And they found that    Compound (I) possesses an excellent apoptosis inhibitory effect and    macrophage migration-inhibitory factor binding ability, and it    possesses the excellent property as a drug for preventing and/or    treating cardiac insufficiency syndrome. On the basis of the above    findings, the inventors completed this invention.

That is, this invention relates to

-   [1] Compound (I);-   [2] Compound (I) described in the above [1], wherein R² is pyridyl,    furyl, thienyl, pyrrolyl, quinolyl, pyrazinyl, pyrimidinyl,    pyridazinyl or indolyl, each of which may have substituents;-   [3] the compound described in the above [1], wherein the compound is    represented by the formula:    wherein R^(1a) is a hydrogen atom, a halogen atom, optionally    halogenated alkyl or optionally halogenated alkoxy; R² has the same    meaning as described in the above [1];-   [4] Compound (I) described in the above [1], wherein R¹ is a halogen    atom, hydroxy, nitro, optionally halogenated alkyl, alkoxy    optionally having substituents, acyl or amino optionally having    substituents;-   [5] Compound (I) described in the above [1], wherein R¹ is a    hydrogen atom;-   [6] Compound (I) described in the above [1], wherein the “pyridyl    which may have substituents” is pyridyl which has substituents;-   [7] Compound (I) described in the above [1], wherein R¹ is a    hydrogen atom; the “pyridyl which may have substituents” is pyridyl    which has substituents;-   [8] Compound (I) described in the above [1], wherein R¹ is a halogen    atom;-   [9] Compound (I) described in the above [1], wherein R² is pyridyl    which may have substituents;-   [10] Compound (I) described in the above [1], wherein R² is pyridyl    which has substituents;-   [11] Compound (I) described in the above [1], wherein R² is 2- or    4-pyridyl which may have substituents;-   [12] Compound (I) described in the above [1], wherein R² is pyridyl,    furyl, thienyl, pyrrolyl, quinolyl, pyrazinyl, pyrimidinyl, indolyl,    tetrahydroquinolyl or thiazolyl, each of which may have    substituents;-   [13] Compound (I) described in the above [1], wherein R² is pyridyl,    furyl, thienyl, pyrrolyl, quinolyl, pyrazinyl, pyrimidinyl,    pyridazinyl, indolyl, tetrahydroquinolyl or thiazolyl, each of which    may have 1 to 3 substituent (s) selected from the group consisting    of-   (1) a halogen atom,-   (2) a C₁₋₆ alkyl which may have 1 to 5 substituent(s) selected from    the group consisting of (i) a halogen atom, (ii) hydroxy, (iii)    carboxy, (iv) cyano, (v) carboxy-C₁₋₆ alkoxy, (vi) C₁₋₆    alkoxy-C₁₋₆alkoxy, (vii) C₁₋₆ alkoxy-carbonyl-C₁₋₆alkoxy, (viii)    C₁₋₆ alkyl-carbonyloxy, (ix) C₁₋₆ alkoxy-carbonyl, (x) carbamoyl    which may have 1 or 2 substituent(s) selected from the group    consisting of (a) mono- or di-C₁₋₆ alkyl which may have carboxy, (b)    C₁₋₆ alkylsulfonyl and (c) C₆₋₁₀ arylsulfonyl, (xi) 5- or 6-membered    saturated cyclic amino-carbonyl which may have carboxy, (xii)    C₁₋₆alkylthio which may have C₁₋₆alkoxy-carbonyl, (xiii) C₁₋₆    alkylsulfinyl which may have C₁₋₆ alkoxy-carbonyl, (xiv)    C₁₋₆alkylsulfonyl which may have C₁₋₆alkoxy-carbonyl, (xv) C₇₋₁₂    aralkylthio, (xvi) C₇₋₁₂ aralkylsulfinyl, (xvii) C₇₋₁₂    aralkylsulfonyl, (xviii) (5- or 6-membered aromatic    heterocycle)-thio, (xix) amino which may have 1 or 2 substituent(s)    selected from the group consisting of (a) C₁₋₆ alkyl, (b) C₁₋₆    alkoxy-carbonyl, (c) optionally halogenated C₁₋₆ alkyl-carbonyl, (d)    C₆₋₁₀ aryl-carbonyl, (e) thienylcarbonyl, (f) C₁₋₆ alkylthio-C₁₋₆    alkyl-carbonyl, (g) mono- or di-C₁₋₆ alkyl-carbamoyl, (h) C₁₋₆    alkylsulfonyl, (i) C₆₋₁₀ arylsulfonyl, (j) di-C₁₋₆    alkylphosphono, (k) di-C₁₋₆ alkylthiophosphono and (1) C₆₋₁₀    aryl-carbamoyl, (xx) phthalimido, (xxi) C₁₋₆    alkylsulfonyloxy, (xxii) 5- or 6-membered aromatic heterocyclic    group, (xxiii) phosphono which may have C₁₋₆ alkyl, (xxiv) 5- to    7-membered saturated cyclic amino which may have 1 or 2    substituent(s) selected from the group consisting of (a) C₇₋₁₂    aralkyl, (b) optionally halogenated C₆₋₁₀ aryl and (c) hydroxy    and (xxv) (5- to 7-membered cyclic amino)-carbonyl,-   (3) C₁₋₆ alkenyl which may have carboxy or C₁₋₆ alkoxy-carbonyl,-   (4) C₆₋₁₀ aryl which may have C₁₋₆ alkoxy,-   (5) C₁₋₆ alkoxy which may have substituents selected from the group    consisting of C₁₋₆alkoxy, C₁₋₆ alkoxy-carbonyl, phthalimido, di-C₁₋₆    alkylsulfonamido and di-C₁₋₆ alkylaminomethylenesulfonamido,-   (6) C₆₋₁₀ aryloxy which may have C₁₋₆ alkylthio,-   (7) C₇₋₁₂ aralkyloxy,-   (8) C₁₋₆ alkylthio which may have substituents selected from the    group consisting of mono- or di-C₁₋₆ alkylamino, carboxy, carbamoyl    and C₁₋₆ alkoxy-carbonyl,-   (9) C₁₋₆ alkylsulfinyl which may have substituents selected from the    group consisting of mono- or di-C₁₋₆ alkylamino, carboxy, carbamoyl    and C₁₋₆ alkoxy-carbonyl,-   (10) C₁₋₆alkylsulfonyl which may have substituents selected from the    group consisting of mono- or di-C₁₋₆ alkylamino, carboxy, and C₁₋₆    alkoxy-carbonyl,-   (11) C₆₋₁₀ arylthio which may have substituents selected from the    group consisting of halogen atom, C₁₋₆ alkyl and C₁₋₆    alkoxy-carbonyl,-   (12) C₆₋₁₀ arylsulfinyl which may have C₁₋₆ alkyl,-   (13) C₆₋₁₀ arylsulfonyl which may have C₁₋₆ alkyl,-   (14) carboxy,-   (15) C₁₋₆ alkoxy-carbonyl,-   (16) C₇₋₁₂ aralkylthio,-   (17) C₇₋₁₂ aralkylsulfinyl,-   (18) C₇₋₁₂ aralkylsulfonyl,-   (19) amino which may have 1 or 2 substituent(s) selected from the    group consisting of C₁₋₆ alkyl, C₇₋₁₂ aralkyl, C₁₋₆ alkoxy-C₁₋₆    alkyl, C₁₋₆ alkoxy-carbonyl, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl,    carboxy-C₁₋₆ alkyl, C₁₋₆ alkyl-carbonyl, C₆₋₁₀ aryl-carbonyl, C₃₋₆    cycloalkyl-carbonyl, thienylcarbonyl, furylcarbonyl and mono- or    di-C₁₋₆ alkylamino-carbonyl,-   (20) 5- to 7-membered saturated cyclic amino which may have    substituents selected from the group consisting of (i) optionally    halogenated C₆₋₁₀ aryl, (ii) C₇₋₁₂ aralkyl, (iii) hydroxy, (iv) C₁₋₆    alkyl which may have C₁₋₆ alkoxy-carbonyl or carboxy, (v) oxo, (vi)    C₁₋₆ alkyl-carbonyl, (vii) C₆₋₁₀ aryl-carbonyl and (viii) C₁₋₆    alkoxy-carbonyl,-   (21) carbamoyl which may have substituents selected from the group    consisting of (i) C₁₋₆ alkyl which may have substituents selected    from the group consisting of halogen atom, C₁₋₆ alkoxy, amino, C₁₋₆    alkoxy-carboxamido and hydroxy, (ii) C₇₋₁₂ aralkyl and (iii) mono-    or di-C₁₋₆ alkylamino-carbonyl,-   (22) (5- to 7-membered cyclic amino)-carbonyl,-   (23) 5- or 6-membered aromatic heterocyclic group which may have    C₁₋₆ alkyl,-   (24) cyano,-   (25) (5- to 10-membered aromatic heterocycle)-thio which may have    C₁₋₆ alkyl,-   (26) C₁₋₆ alkylcarbonyl and-   (27) oxo;-   [14] Compound (I) described in the above [1] or [3], wherein R² is    optionally N-oxidized pyridyl which may have 1 to 3 substituent(s)    selected from the group consisting of-   (1) a halogen atom,-   (2) a C₁₋₆ alkyl which may have substituents selected from the group    consisting of a halogen atom, C₁₋₆ alkyl-carbonyloxy, C₁₋₆    alkoxy-C₁₋₆ alkoxy, hydroxy, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkoxy,    carboxy-C₁₋₆alkoxy, carboxy, C₁₋₆alkoxy-carbonyl, C₁₋₆alkylthio,    C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfonyloxy, 5- or    6-membered saturated cyclic amino, C₁₋₆ alkylsulfonyl-carbamoyl,    C₆₋₁₀ arylsulfonyl-carbamoyl and (5- to 7-membered cyclic    amino)-carbonyl,-   (3) C₂₋₆ alkenyl which may have carboxy or C₁₋₆ alkoxy-carbonyl,-   (4) C₆₋₁₀ aryl,-   (5) C₁₋₆ alkoxy which may have substituents selected from the group    consisting of C₁₋₆alkoxy, C₁₋₆alkoxy-carbonyl, phthalimido, di-C₁₋₆    alkylsulfonamido and di-C₁₋₆ alkylaminomethylenesulfonamido,-   (6) C₆₋₁₀ aryloxy which may have C₁₋₆ alkylthio,-   (7) C₇₋₁₂ aralkyloxy,-   (8) C₁₋₆ alkylthio which may have mono- or di-C₁₋₆ alkylamino or    C₁₋₆ alkoxy-carbonyl,-   (9) C₁₋₆ alkylsulfinyl which may have mono- or di-C₁₋₆alkylamino,-   (10) C₁₋₆alkylsulfonyl which may have mono- or di-C₁₋₆ alkylamino,-   (11) C₆₋₁₀ arylthio which may have substituents selected from the    group consisting of halogen atom, C₁₋₆ alkyl and C₁₋₆    alkoxy-carbonyl,-   (12) C₆₋₁₀ arylsulfinyl which may have C₁₋₆ alkyl,-   (13) C₆₋₁₀ arylsulfonyl which may have C₁₋₆ alkyl,-   (14) carboxy,-   (15) C₁₋₆ alkoxy-carbonyl,-   (16) C₇₋₁₂ aralkylthio,-   (17) C₇₋₁₂ aralkylsulfinyl,-   (18) C₇₋₁₂ aralkylsulfonyl,-   (19) amino which may have substituents selected from the group    consisting of C₁₋₆ alkyl, C₇₋₁₂ aralkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl,    C₁₋₆ alkoxy-carbonyl, C₁₋₆ alkyl-carbonyl, C₆₋₁₀ aryl-carbonyl, C₃₋₆    cycloalkyl-carbonyl, thienylcarbonyl, furylcarbonyl and mono- or    di-C₁₋₆ alkylamino-carbonyl,-   (20) 5- to 7-membered saturated cyclic amino which may have    substituents selected from the group consisting of optionally    halogenated C₆₋₁₀ aryl, C₁₋₆alkyl-carbonyl, C₆₋₁₀ aryl-carbonyl and    C₁₋₆ alkoxy-carbonyl,-   (21) carbamoyl which may have substituents selected from the group    consisting of (i) C₁₋₆ alkyl which may have substituents selected    from the group consisting of halogen atom, C₁₋₆ alkoxy, amino and    C₁₋₆ alkoxy-carboxamido, (ii) C₇₋₁₂ aralkyl and (iii) mono- or    di-C₁₋₆ alkylamino-carbonyl,-   (22) (5- to 7-membered cyclic amino)-carbonyl,-   (23) pyridyl, thienyl, furyl, pyrazolyl or oxazolyl, each of which    may have C₁₋₆ alkyl and (24) oxo;-   [15] Compound (I) described in the above [1], wherein R² is furyl,    thienyl, pyrrolyl, quinolyl, pyrazinyl, pyrimidinyl, indolyl,    tetrahydroquinolyl or thiazolyl, each of which may have 1 or 2    substituent(s) selected from (1) C₁₋₆ alkyl, (2) amino which may    have 1 or 2 substituent (s) selected from the group consisting of    C₁₋₆alkyl, C₁₋₆alkoxy-carbonyl, C₁₋₆alkoxy-carbonyl-C₁₋₆alkyl and    carboxy-C₁₋₆ alkyl, (3) C₁₋₆ alkylsulfonyl and (4) mono- or di-C₁₋₆    alkylamino-C₁₋₆ alkylthio;-   [16] Compound (I) described in the above [1], wherein R² is pyridyl    which may have 1 or 2 substituent(s) selected from the group    consisting of-   (1) C₁₋₆ alkyl which may have substituents selected from the group    consisting of C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkoxy, carboxy-C₁₋₆ alkoxy,    carboxy, C₁₋₆ alkoxy-carbonyl and C₁₋₆ alkylsulfonyloxy,-   (2) C₂₋₆ alkenyl which may have carboxy or C₁₋₆ alkoxy-carbonyl,-   (3) C₁₋₆ alkylthio which may have mono- or di-C₁₋₆ alkylamino or    C₁₋₆ alkoxy-carbonyl,-   (4) C₁₋₆alkylsulfinyl which may have mono- or di-C₁₋₆alkylamino,-   (5) C₁₋₆alkylsulfonyl which may have mono- or di-C₁₋₆ alkylamino,-   (6) C₇₋₁₂ aralkylthio,-   (7) C₇₋₁₂ aralkylsulfinyl,-   (8) C₇₋₁₂ aralkylsulfonyl,-   (9) carbamoyl which may have substituents selected from the group    consisting of (i) C₁₋₆ alkyl which may have substituents selected    from the group consisting of halogen atom, C₁₋₆ alkoxy and    amino, (ii) C₇₋₁₂ aralkyl and (iii) mono- or di-C₁₋₆    alkylamino-carbonyl and-   (10) (5- to 7-membered cyclic amino)-carbonyl;-   [17] Compound (I) described in the above [1], wherein R¹-   (1) a hydrogen atom, (2) a halogen atom, (3) hydroxy, (4) optionally    halogenated C₁₋₆ alkyl, (5) C₁₋₆ alkoxy which may have substituents    selected from the group consisting of carboxy, hydroxy, C₁₋₆    alkoxy-carbonyl and C₆₋₁₀ aryl, (6) C₁₋₆ alkyl-carbamoyl, (7) C₃₋₆    cycloalkyl-carbamoyl, (8) (5- or 6-membered saturated cyclic    amino)-carbonyl or (9) carboxy;-   [18] Compound (I) described in the above [16], wherein R¹ is a    hydrogen atom or a halogen atom;-   [19] Compound (I) described in the above [1], wherein R¹ is a    halogen atom or a hydrogen atom, R² is pyridyl which may have 1 or 2    substituent(s) selected from the group consisting of C₁₋₆ alkyl,    carboxy-C₁₋₆ alkyl and C₁₋₆ alkylsulfonyl;-   [20]-   3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propionic acid,-   3-[6-(7-chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-4-methyl-2-p    yridyl]propionic acid,-   3-[2-(7-chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]pr opionic    acid,-   3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propionic acid,-   3-[2-methyl-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]pr opionic    acid,-   3-[2-(7-chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-6-methyl-4-p    yridyl]propionic acid or salts thereof;-   [21] Compound (I) described in the above [1], which has an ability    to bind macrophage migration-inhibitory factor;-   [22] a pharmaceutical, which comprises a compound described in-   [1], a salt thereof or prodrug thereof;-   [23] the pharmaceutical described in the above [22], which is a    pharmaceutical for inhibition of apoptosis or protection of cells;-   [24] the pharmaceutical described in the above [22], which is a    pharmaceutical for inhibition of apoptosis;-   [25] the pharmaceutical described in the above [23], which is a    pharmaceutical for inhibition of heart muscle cells apoptosis;-   [26] the pharmaceutical described in the above [22], which is a    pharmaceutical for preventing and/or treating apoptosis derived    diseases;-   [27] the pharmaceutical described in the above [22], which is a    pharmaceutical for preventing and/or treating macrophage    migration-inhibitory factor derived diseases;-   [28] the pharmaceutical described in the above [22], which is a    pharmaceutical for preventing and/or treating circulatory disease,    bone and articular disease, infectious disease, inflammatory bowel    disease or kidney disease;-   [29] a method for preventing and/or treating circulatory disease,    bone and articular disease, infectious disease, inflammatory bowel    disease or kidney disease, which comprises administering an    effective amount of the compound described in the above [1], a salt    thereof or a prodrug thereof to a mammal;-   [30] use of the compound described in the above [1], a salt thereof    or a prodrug thereof for producing a pharmaceutical for preventing    and/or treating circulatory disease, bone and articular disease,    infectious disease, inflammatory bowel disease or kidney disease;    and the like.

BEST MODE FOR CARRYING OUT THE INVENTION

In the above formula, R¹ represents a hydrogen atom, a halogen atom,hydroxy, nitro, optionally halogenated alkyl, alkoxy which may havesubstituents, acyl or amino which may have substituents.

Examples of the “halogen atom” represented by R¹ are fluorine, chlorine,bromine, iodine and the like.

Examples of the “optionally halogenated alkyl” represented by R¹ arealkyl (e.g., C₁₋₆alkyl such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like) which mayhave 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine,bromine, iodine and the like), and the like. Concrete examples aremethyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl,3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl and the like.

Examples of the “alkoxy” of “alkoxy which may have substituents”represented by R¹ are C₁₋₈ alkoxy such as methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, and thelike.

Examples of the “substituent” of “alkoxy which may have substituents”represented by R¹ are the same as the “substituent” of “hydrocarbongroup which may have substituents” represented by R³ described below andthe like. And the number of the substituent is 1 to 3 and thesubstitution can be occurred at the position which is possible to besubstituted.

Examples of “acyl” represented by R¹ are acyl represented by theformula: —(C═O)—R³, —(C═O)—OR³, —(C═O)—NR³R⁴, —(C═S)—NHR³, —SO—R⁵,—SO₂—R⁵ or —SO₂—NHR³ wherein R³ is a hydrogen atom, hydrocarbon groupwhich may have substituents or heterocyclic group which nay havesubstituents; R⁴ is a hydrogen atom or C₁₋₆ alkyl; R⁵ is hydrocarbongroup which may have substituents or heterocyclic group which may havesubstituents, and the like.

In the above formula, examples of the “hydrocarbon group” of the“hydrocarbon group which may have substituents” are chain or cyclichydrocarbon group (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, aryl,aralkyl, and the like), and the like. Among them, chain or cyclichydrocarbon group having 1 to 16 carbon atoms and the like arepreferable.

AS the “alkyl”, C₁₋₆alkyl (e.g., methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like) andthe like are preferable.

As the “alkenyl”, C₂₋₆ alkenyl (e.g., vinyl, allyl, isopropenyl,1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl,1-methyl-2-propenyl, 2-methyl-1-propenyl, and the like) and the like arepreferable.

As the “alkynyl”, C₂₋₆alkynyl (e.g., ethynyl, propargyl, 1-butynyl,2-butynyl, 3-butynyl, 1-hexynyl, and the like) and the like arepreferable.

As the “cycloalkyl”, C₃₋₆ cycloalkyl (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and the like) and the like are preferable.

As the “aryl”, C₆₋₁₄ aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl,2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl, and the like), andthe like are preferable.

As the “aralkyl”, C₇₋₁₆ aralkyl (e.g., benzyl, phenethyl,diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl,3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, and the like) and thelike are preferable.

Examples of the “substituent” of “hydrocarbon group which may havesubstituents” represented by R³ are halogen atom (e.g., fluorine,chlorine, bromine, iodine, and the like), C₁₋₃ alkylenedioxy (e.g.,methylenedioxy, ethylenedioxy, and the like), nitro, cyano, optionallyhalogenated C₁₋₆ alkyl, optionally halogenated C₂₋₆ alkenyl,carboxy-C₂₋₆ alkenyl (e.g., 2-carboxyethenyl, 2-carboxy-2-methylethenyl,and the like), optionally halogenated C₂₋₆ alkynyl, optionallyhalogenated C₃₋₆ cycloalkyl, C₆₋₁₄ aryl (e.g., phenyl, 1-naphthyl,2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl, and thelike), optionally halogenated C₁₋₈ alkoxy, C₁₋₆alkoxy-carbonyl-C₁₋₆alkoxy (e.g., ethoxycarbonylmethyloxy, and thelike), hydroxy, C₆₋₁₄ aryloxy (e.g., phenyloxy, 1-naphthyloxy,2-naphthyloxy, and the like), C₇₋₁₆ aralkyloxy (e.g., benzyloxy,phenethyloxy, and the like), mercapto, optionally halogenatedC₁₋₆alkylthio, C₆₋₁₄ arylthio (e.g., phenylthio, 1-naphthylthio,2-naphthylthio, and the like), C₇₋₁₆ aralkylthio (e.g., benzylthio,phenethylthio, and the like), amino, mono-C₁₋₆ alkylamino (e.g.,methylamino, ethylamino, and the like), mono-C₆₋₁₄ arylamino (e.g.,phenylamino, 1-naphthylamino, 2-naphthylamino, and the like), di-C₁₋₆alkylamino (e.g., dimethylamino, diethylamino, ethylmethylamino, and thelike), di-C₆₋₁₄ arylamino (e.g., diphenylamino, and the like), formyl,carboxy, C₁₋₆ alkyl-carbonyl (e.g., acetyl, propionyl, and the like),C₃₋₆ cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl,cyclopentylcarbonyl, cyclohexylcarbonyl, and the like), C₁₋₆alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,tert-butoxycarbonyl, and the like), C₆₋₁₄ aryl-carbonyl (e.g., benzoyl,1-naphthoyl, 2-naphthoyl, and the like), C₇₋₁₆ aralkyl-carbonyl (e.g.,phenylacetyl, 3-phenylpropionyl, and the like), C₆₋₁₄ aryloxy-carbonyl(e.g., phenoxycarbonyl, and the like), C₇₋₁₆ aralkyloxy-carbonyl (e.g.,benzyloxycarbonyl, phenethyloxycarbonyl, and the like), (5- or6-membered heterocycle)-carbonyl (e.g., nicotinoyl, isonicotinoyl,thenoyl, furoyl, morpholinocarbonyl, thiomorpholinocarbonyl,piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, and the like),carbamoyl, mono-C₁₋₆ alkyl-carbamoyl (e.g., methylcarbamoyl,ethylcarbamoyl, and the like), di-C₁₋₆ alkyl-carbamoyl (e.g.,dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, and thelike), C₆₋₁₄ aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl,2-naphthylcarbamoyl, and the like), (5- or 6-memberedheterocycle)-carbamoyl (e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl,4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl, and thelike), C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, and thelike), C₆₋₁₄ arylsulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl,2-naphthylsulfonyl, and the like), formylamino, C₁₋₆ alkyl-carbonylamino(e.g., acetylamino, and the like), C₆₋₁₄ aryl-carbonylamino (e.g.,benzoylamino, naphthoylamino, and the like), C₁₋₆ alkoxy-carbonylamino(e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,butoxycarbonylamino, and the like), C₁₋₆ alkylsulfonylamino (e.g.,methylsulfonylamino, ethylsulfonylamino, and the like), C₆₋₁₄arylsulfonylamino (e.g., phenylsulfonylamino, 2-naphthylsulfonylamino,1-naphthylsulfonylamino, and the like), C₁₋₆alkyl-carbonyloxy (e.g.,acetoxy, propionyloxy, and the like), C₆₋₁₄ aryl-carbonyloxy (e.g.,benzoyloxy, naphthylcarbonyloxy, and the like), C₁₋₆ alkoxy-carbonyloxy(e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy,butoxycarbonyloxy, and the like), mono-C₁₋₆ alkyl-carbamoyloxy (e.g.,methylcarbamoyloxy, ethylcarbamoyloxy, and the like), di-C₁₋₆alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy, andthe like), C₆₋₁₄ aryl-carbamoyloxy (e.g., phenylcarbamoyloxy,naphthylcarbamoyloxy, and the like), nicotinoyloxy, 5- to 7-memberedsaturated cyclic amino which may have substituents, 5- to 10-memberedaromatic heterocyclic group (e.g., 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl,8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl,1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl,3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl, and the like),sulfo, and the like.

The “hydrocarbon group” may have 1 to 5, preferably 1 to 3substituent(s) at the position which is possible to be substituted. Andwhen the number of the substituents 2 or more, each substituent can besame or different.

Examples of the “optionally halogenated C₁₋₆ alkyl” described above arealkyl (e.g., C₁₋₆alkyl such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like) which mayhave 1 to 5, preferably 1 to 3 halogen atom(s) (e.g., fluorine,chlorine, bromine, iodine, and the like), and the like. Concreteexamples are methyl, chloromethyl, difluoromethyl, trichloromethyl,trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl,pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl,4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyland the like.

Examples of the “optionally halogenated C₂₋₆ alkenyl” described aboveare C₂₋₆ alkenyl (e.g., vinyl, propenyl, isopropenyl, 2-buten-1-yl,4-penten-1-yl, 5-hexen-1-yl, and the like) which may have 1 to 5,preferably 1 to 3 halogen atom(s) (e.g., fluorine, chlorine, bromine,iodine, and the like), and the like.

Examples of the “optionally halogenated C₂₋₆ alkynyl” described aboveare C₂₋₆ alkynyl (e.g., 2-butyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl, andthe like) which may have 1 to 5, preferably 1 to 3 halogen atom(s)(e.g., fluorine, chlorine, bromine, iodine, and the like), and the like.

Examples of the “optionally halogenated C₃₋₆ cycloalkyl” described aboveare C₃₋₆ cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and the like) which may have 1 to 5, preferably 1 to 3halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine, and thelike), and the like. Concrete examples are cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl,2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl, and the like.

Examples of the “optionally halogenated C₁₋₈ alkoxy” are C₁₋₈alkoxy(e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, pentyloxy, hexyloxy, and the like) which may have 1 to 5,preferably 1 to 3 halogen atom(s) (e.g., fluorine, chlorine, bromine,iodine, and the like), and the like. Concrete examples are methoxy,difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy,propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy,sec-butoxy, pentyloxy, hexyloxy, and the like.

Examples of the “optionally halogenated C₁₋₆ alkylthio” are C₁₋₆alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio,butylthio, sec-butylthio, tert-butylthio, and the like) which may have 1to 5, preferably 1 to 3 halogen atom(s) (e.g., fluorine, chlorine,bromine, iodine, and the like), and the like. Concrete examples aremethylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,pentylthio, hexylthio, and the like.

Examples of the “5- to 7-membered saturated cyclic amino” of the “5- to7-membered saturated cyclic amino which may have substituents” describedabove are 5- to 7-membered saturated cyclic amino which may contain 1 to4 heteroatom(s) selected 1 or 2 kind(s) from nitrogen atom, sulfur atomand oxygen atom in addition to one nitrogen atom and carbon atom(s).Concrete examples are pyrrolidin-1-yl, piperidino, piperadin-1-yl,morpholino, thiomorpholino, tetrahydroazepin-1-yl, and the like.

Examples of the “substituent” of the “5- to 7-membered saturated cyclicamino which may have substituents” described above are C₁₋₆ alkyl (e.g.,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl, and the like), C₆₋₁₄ aryl (e.g., phenyl,1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl,2-anthryl, and the like), C₁₋₆ alkyl-carbonyl (e.g., acetyl, propionyl,and the like), 5- to 10-membered aromatic heterocyclic group (e.g.,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl,3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl,3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl,2-benzo[b]furanyl, 3-benzo [b]furanyl, and the like), oxo and the like.The number of the substituent is 1 to 3.

Examples of the “heterocyclic group” of the “heterocyclic group whichmay have substituents” represented by R³ are monovalent group producedby removing any one of hydrogen atom from 5- to 14-membered (monocyclic,bicyclic or tricyclic) heterocycle containing 1 to 4 heteroatom(s)selected 1 or 2 kind(s) from nitrogen atom, sulfur atom and oxygen atomin addition to carbon atom(s), and the like. Preferable examples aremonovalent groups produced by removing any one of hydrogen atom from (i)5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle,(ii) 5- to 10-membered non-aromatic heterocycle and (iii) 7- to10-membered bridged heterocycle.

Examples of the “5- to 14-membered (preferably 5- to 10-membered)aromatic heterocycle” described above are aromatic heterocycle such asthiophene, benzo[b]thiophene, benzo[b]furan, benzimidazole, benzoxazole,benzthiazole, benzoisothiazole, naphtho[2,3-b]thiophene, furan, pyrrole,imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole,isoindole, 1H-indazole, purine, 4H-quinolizine, isoquinoline, quinoline,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,carbazole, β-carboline, phenanthridine, acridine, phenazine, thiazole,isothiazole, phenothiazine, isoxazole, furazane, phenoxazine, and thelike; or the ring produced by condensing the aromatic heterocycle(preferably monocyclic heterocycle) with 1 or more (preferably 1 or 2)aromatic ring(s) (e.g., benzene ring, and the like); and the like.

Examples of the “5- to 10-membered non-aromatic heterocycle” describedabove are pyrrolidine, imidazoline, pyrazolidine, pyrazoline,piperidine, piperazine, morpholine, thiomorpholine, dioxazole,oxadiazoline, thiadiazoline, triazoline, thiadiazole, dithiazole, andthe like.

Examples of the “7- to 10-membered bridged heterocycle” described aboveare quinuclidine, 7-azabicyclo[2.2.1] heptane, and the like.

Preferable examples of the “heterocyclic group” are 5 to 14-membered(preferably 5- to 10-membered) (monocyclic or bicyclic) heterocyclicgroup containing 1 to 4 heteroatom(s) selected 1 or 2 kind(s) fromnitrogen atom, sulfur atom and oxygen atom in addition to carbonatom(s). Concrete examples are aromatic heterocyclic group such as2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl,1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, pyrazinyl,2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl,3-isothiazolyl, 3-isoxazolyl, 1-indolyl, 2-indolyl, 3-indolyl,2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b)thienyl,2-benzo[b]furanyl, 3-benzo[b]furanyl, and the like; non-aromaticheterocyclic group such as 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-imidazolinyl, 4-imidazolinyl, 2-pyrazolidinyl,3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl,4-piperidyl, 1-piperazinyl, 2-piperazinyl, morpholino, thiomorpholino,and the like.

Among them, 5-or 6-membered heterocyclic group containing 1 to 3heteroatom(s) selected from nitrogen atom, sulfur atom and oxygen atomin addition to carbon atom(s) and the like are more preferable. Concreteexamples are 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-furyl, 3-furyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl,3-isothiazolyl, 3-isoxazolyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-imidazolinyl, 4-imidazolinyl, 2-pyrazolidinyl,3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl,4-piperidyl, 1-piperazinyl, 2-piperazinyl, morpholino, thiomorpholinoand the like.

The “substituent” of the “heterocyclic group which may havesubstituents” has the same meaning as the “substituent” of the“hydrocarbon group which may have substituents” represented by R³described above.

The “heterocyclic group” may have 1 to 5, preferably 1 to 3substituent(s) described above at the position where the substitutioncan be possible. When the number of the substituent is 2 or more, eachof substituents may be same or different.

Examples of the “C₁₋₆ alkyl” represented by R⁴ are methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyland the like.

The “hydrocarbon group which may have substituents” and “heterocyclicgroup which may have substituents” represented by R⁵ have the samemeaning as “hydrocarbon group which may have substituents” and“heterocyclic group which may have substituents” represented by R³described above, respectively.

As the “substituent” of “amino which may have substituents” representedby R¹, 1 or 2 of the “substituent” of the “hydrocarbon group which mayhave substituents” represented by R³ described above can be exemplified.

Concrete examples of R¹ are (1) a hydrogen atom, (2) a halogen atom, (3)hydroxy, (4) optionally halogenated C₁₋₆alkyl, (5) C₁₋₆ alkoxy which mayhave substituents selected from the group consisting of carboxy,hydroxy, C₁₋₆ alkoxy-carbonyl and C₆₋₁₀ aryl, (6) C₁₋₆alkyl-carbamoyl,(7) C₃₋₆cycloalkyl-carbamoyl, (8) (5- or 6-membered saturated cyclicamino)-carbonyl, and the like.

Preferable examples of R¹ are a hydrogen atom, a halogen atom,optionally halogenated alkyl (preferably C₁₋₆ alkyl), optionallyhalogenated alkoxy (preferably C₁₋₆ alkoxy), and the like. Especially,the preferable example of R¹ is a hydrogen atom.

R² is pyridyl, furyl, thienyl, pyrrolyl, quinolyl, pyrazinyl,pyrimidinyl, pyridazinyl, indolyl, tetrahydroquinolyl or thiazolyl, eachof which may have substituents.

Examples of the “substituent” of the “pyridyl, furyl, thienyl, pyrrolyl,quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl,tetrahydroquinolyl or thiazolyl, each of which may have substituents”represented by R² are (1) halogen atom (e.g., fluorine, chlorine,bromine, iodine, and the like), (2) C₁₋₆alkyl (e.g., methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,hexyl, and the like) which may have substituents, (3) C₁₋₆ alkenyl(e.g., vinyl, propenyl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl,5-hexen-1-yl, and the like) which may have substituents, (4) C₆₋₁₀ aryl(e.g., phenyl, 1-naphthyl, 2-naphthyl, and the like) which may havesubstituents, (5) C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, and thelike) which may have substituents, (6) C₆₋₁₀ aryloxy (e.g., phenyloxy,1-naphthyloxy, 2-naphthyloxy, and the like) which may have substituents,(7) C₇₋₁₂ aralkyloxy (e.g., benzyloxy, phenethyloxy, and the like) whichmay have substituents, (8) C₁₋₆ alkylthio (e.g., methylthio, ethylthio,propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, andthe like) which may have substituents, (9) C₁₋₆ alkylsulfinyl (e.g.,methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl,butylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, and the like)which may have substituents, (10) C₁₋₆ alkylsulfonyl (e.g.,methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl,butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, and the like)which may have substituents, (11) C₆₋₁₀ arylthio (e.g., phenylthio,1-naphthylthio, 2-naphthylthio, and the like) which may havesubstituents, (12) C₆₋₁₀ arylsulfinyl (e.g., phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl, and the like) which may havesubstituents, (13) C₆₋₁₀ arylsulfonyl (e.g., phenylsulfonyl,1-naphthylsulfonyl, 2-naphthylsulfonyl, and the like) which may havesubstituents, (14) carboxy, (15) C₁₋₆ alkoxy-carbonyl (e.g.,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, andthe like) which may have substituents, (16) C₇₋₁₂ aralkylthio (e.g.,benzylthio, phenethylthio, and the like) which may have substituents,(17) C₇₋₁₂ aralkylsulfinyl (e.g., benzylsulfinyl, phenethylsulfinyl, andthe like) which may have substituents, (18) C₇₋₁₂ aralkylsulfonyl (e.g.,benzylsulfonyl, phenethylsulfonyl, and the like) which may havesubstituents, (19) amino which may have substituents, (20) 5- to7-membered (preferably 5- or 6-membered) saturated cyclic amino (e.g.,pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, thiomorpholino,imidazolidinyl, and the like) which may have substituents, (21)carbamoyl which may have substituents, (22) (5- to 7-membered cyclicamino)-carbonyl (e.g., pyrrolidin-1-ylcarbonyl, and the like) which mayhave substituents, (23) 5- to 10-membered (preferably 5- or 6-membered)aromatic heterocyclic group (e.g., 2-thienyl, 3-thienyl, 2-furyl,3-furyl, 1-pyrazoly, 3-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,5-oxazolyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl,1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl,2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl,3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl, and the like)which may have substituents, (24) (5- to 10-membered aromaticheterocyclic group)-thio (e.g., 4-pyridylthio, 2-pyrimidinylthio, andthe like) which may have substituents, (25) C₁₋₆ alkylcarbonyl which mayhave substituents, (26) oxo, (27) cyano, and the like. And the number ofthe substituent is 1 to 5, preferably, 1 to 3. The preferablesubstituent is C₁₋₆ alkyl which may have substituents.

Examples of the “substituent” of the above described. (2)-(13),(15)-(25) are

-   (i) halogen atom (e.g., fluorine, chlorine, bromine, iodine, and the    like),-   (ii) hydroxy,-   (iii) carboxy,-   (iv) cyano,-   (v) C₁₋₆ alkyl which may have 1 to 3 substituent(s) selected from    the group consisting of (a) halogen atom, (b) C₁₋₆ alkoxy, (c)    amino, (d) C₁₋₆alkoxy-carboxamido, (e) C₁₋₆ alkoxy-carbonyl, (f)    hydroxy and (g) carboxy (e.g., methyl, chloromethyl, difluoromethyl,    trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,    2,2,2-trofluoroethyl, pentafluoroethyl, propyl,    3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl,    isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,    5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl, aminomethyl,    2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl,    6-aminohexyl, methoxyethyl, 2,2-dimethoxyethyl, 6,6-dimethoxyhexyl,    methoxycarbonylmethyl, hydroxymethyl, carboxymethyl,    butoxycarbonylmethyl, and the like),-   (vi) optionally halogenated C₆₋₁₀ aryl (e.g., phenyl,    4-fluorophenyl, 4-chlorophenyl, and the like),-   (vii) C₇₋₁₂ aralkyl (e.g., benzyl, phenethyl, diphenylmethyl,    1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl,    3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, and the like),-   (viii) C₁₋₆alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, and the    like),-   (ix) C₁₋₆alkoxy-C₁₋₆alkoxy (e.g., methoxymethoxy, ethoxymethoxy,    propoxymethoxy, butoxymethoxy, and the like),-   (x) C₁₋₆alkyl-carbonyloxy (e.g., acetoxy, propionyloxy, and the    like),-   (xi) carboxy-C₁₋₆alkoxy (e.g., carboxymethoxy, 2-carboxyethoxy, and    the like),-   (xii) C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkoxy (e.g.,    methoxycarbonylmethoxy, methoxycarbonylethoxy, ethoxycarbonylethoxy,    butoxycarbonylethoxy, tert-butoxycarbonylethoxy, and the like),-   (xiii) C₁₋₆ alkylsulfonyloxy (e.g., methylsulfonyloxy,    ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy,    butylsulfonyloxy, sec-butylsulfonyloxy, tert-butylsulfonyloxy, and    the like),-   (xiv) C₁₋₆ alkyl-carbonyl (e.g., acetyl, propionyl, and the like),-   (xv) C₆₋₁₀ aryl-carbonyl (e.g., benzoyl, naphthylcarbonyl, and the    like),-   (xvi) C₃₋₆ cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl,    cyclopentylcarbonyl, cyclohexylcarbonyl, and the like),-   (xvii) C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,    propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, and the like),-   (xviii) mono- or di-C₁₋₆ alkylaminocarbonyl (e.g.,    methylaminocarbonyl, ethylaminocarbonyl, dimethylaminocarbonyl,    diethylaminocarbonyl, and the like),-   (xix) (5- or 6-membered aromatic heterocycle)-carbonyl (e.g.,    thienylcarbonyl, furylcarbonyl, and the like),-   (xx) mono-or di-C₁₋₆alkyl-carbamoyl which may have carboxy (e.g.,    methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl,    diethylcarbamoyl, ethylmethylcarbamoyl, carboxymethylcarbamoyl,    methoxycarbonylmethylcarbamoyl, carboxymethyl(methyl)carbamoyl, and    the like),-   (xxi) (5- or 6-membered saturated cyclic amino)-carbonyl which may    have carboxy (e.g., carboxypyrrolidinylcarbonyl, and the like),    C₆₋₁₀ arylamino-carbonyl or (5- to 7-membered cyclic    amino)-carbonyl,-   (xxii) C₁₋₆ alkylthio which may have C₁₋₆alkoxy-carbonyl or mono- or    di-C₁₋₆ alkylamino (e.g., methylthio, ethylthio, propylthio,    isopropylthio, butylthio, sec-butylthio, tert-butylthio,    methoxycarbonylmethylthio, and the like),-   (xxiii) C₁₋₆ alkylsulfinyl which may have C₁₋₆ alkoxy-carbonyl    (e.g., methylsulfinyl, ethylsulfinyl, propylsulfinyl,    isopropylsulfinyl, butylsulfinyl, sec-butylsulfinyl,    tert-butylsulfinyl, methoxycarbonylmethylsulfinyl, and the like),-   (xxiv) C₁₋₆ alkylsulfonyl which may have C₁₋₆ alkoxy-carbonyl (e.g.,    methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl,    butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl,    methoxycarbonylmethylsulfonyl, and the like),-   (xxv) C₇₋₁₂ aralkylthio (e.g., benzylthio, phenethylthio, and the    like),-   (xxvi) C₇₋₁₂ aralkylsulfinyl (e.g., benzylsulfinyl,    phenethylsulfinyl, and the like),-   (xxvii) C₇₋₁₂ aralkylsulfonyl (e.g., benzylsulfonyl,    phenethylsulfonyl, and the like),-   (xxviii) (5- or 6-membered aromatic heterocycle)-thio (e.g.,    2-pyridylthio, 3-pyridylthio, 4-pyridylthio, and the like),-   (xxix) amino which may have 1 or 2 substituent(s) selected from the    group consisting of (a) C₁₋₆ alkyl, (b) C₁₋₆ alkoxy-carbonyl, (c)    optionally halogenated C₁₋₆ alkyl-carbonyl, (d) C₆₋₁₀    aryl-carbonyl, (e) thienylcarbonyl, (f) C₁₋₆ alkylthio-C₁₋₆    alkyl-carbonyl, (g) mono- or di-C₁₋₆ alkyl-carbamoyl, (h) C₁₋₆    alkylsulfonyl, (i) C₆₋₁₀ arylsulfonyl, (j)    di-C₁₋₆alkylphosphono, (k) di-C₁₋₆alkylthiophosphono and (1) C₆₋₁₀    aryl-carbamoyl (e.g., amino, methylamino, ethylamino, dimethylamino,    diethylamino, ethylmethylamino, tert-butoxycarbonylamino,    acetylamino, propionylamino, butyrylamino, isobutyrylamino,    trifluoroacetylamino, benzoylamino, naphthylcarbonylamino,    thienylcarbonylamino, 3-methylthiopropionylamino, 3-methylureido,    3,3-dimethylureido, methylsulfamoyl, ethylsulfamoyl,    phenylsulfamoyl, diethylphosphonoamino, diethylthiophosphonoamino,    3-phenylureido, 3,3-diethylureido, methylcarbonylamino,    ethylcarbonylamino, propylcarbonylamino, phenylcarbonylamino,    thiophenylcarbonylamino, trifluoromethylcarbonylamino,    methylthioethylcarbonylamino, dimethylaminocarbonylamino,    methylsulfonylamino, ethylsulfonylamino, phenylsulfonylamino,    methylaminocarbonylamino, ethylaminocarbonylamino,    phenylaminocarbonylamino, thiophenylcarbonylamino, and the like),-   (xxx) 5- to 7-membered (preferably 5- or 6-membered) saturated    cyclic amino (e.g., pyrrolidin-1-yl, piperidino, piperazin-1-yl,    morpholino, thiomorpholino, and the like) which may have 1 or 2    substituent(s) selected from the group consisting of (a) C₇₋₁₂    aralkyl, (b) optionally halogenated C₆₋₁₀ aryl and (c) hydroxy,-   (xxxi) phthalimido,-   (xxxii) carbamoyl which may have 1 or 2 substituent(s) selected from    the group consisting of (a) C₁₋₆ alkylsulfonyl and (b) C₆₋₁₀    arylsulfonyl,-   (xxxiii) di-C₁₋₆ alkylsulfonamido (e.g., dimethylsulfonamido, and    the like) or di-C₁₋₆alkylamino-C₁₋₆alkylenesulfonamido (e.g.,    dimethylaminomethylenesulfonamido, and the like),-   (xxxiv) 5- or 6-membered aromatic heterocyclic group (e.g.,    tetrazolyl, oxazolyl, isoxazolyl, and the like),-   (xxxv) phosphono which may have C₁₋₆ alkyl (e.g., phosphono,    diethylphosphono, and the like),-   (xxxvi) oxo, and the like. The number of the substituent is 1 to 3.

The “pyridyl, furyl, thienyl, pyrrolyl, quinolyl, pyrazinyl,pyrimidinyl, pyridazinyl, indolyl, tetrahydroquinolyl or thiazolyl, eachof which may have substituents” represented by R² may have 1 to 3substituent(s) at any position which can be substituted. When the numberof the substituent is 2 or more, each substituent may be same ordifferent.

Preferable examples of R² are pyridyl, furyl, thienyl, pyrrolyl,quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl,tetrahydroquinolyl or thiazolyl (preferably pyridyl, more preferably 2-or 4-pyridyl), each of which has 1 to 3 substituent(s) selected from thegroup consisting of

-   (1) halogen atom,-   (2) C₁₋₆ alkyl which may have 1 to 5 substituent(s) selected from    the group consisting of (i) halogen atom, (ii) hydroxy, (iii)    carboxy, (iv) cyano, (v) carboxy-C₁₋₆alkoxy, (vi) C₁₋₆ alkoxy-C₁₋₆    alkoxy, (vii) C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkoxy, (viii) C₁₋₆    alkyl-carbonyloxy, (ix) C₁₋₆ alkoxy-carbonyl, (x) carbamoyl which    may have 1 or 2 substituent(s) selected from the group consisting    of (a) mono-or di-C₁₋₆ alkyl which may have carboxy, (b) C₁₋₆    alkylsulfonyl and (c) C₆₋₁₀ arylsulfonyl (xi) (5- or 6-membered    saturated cyclic amino)-carbonyl which may have carboxy, (xii)    C₁₋₆alkylthio which may have C₁₋₆alkoxy-carbonyl, (xiii) C₁₋₆    alkylsulfinyl which may have C₁₋₆ alkoxy-carbonyl, (xiv)    C₁₋₆alkylsulfonyl which may have C₁₋₆ alkoxy-carbonyl, (xv) C₇₋₁₂    aralkylthio, (xvi) C₇₋₁₂ aralkylsulfinyl, (xvii) C₇₋₁₂    aralkylsulfonyl, (xviii) (5- or 6-membered aromatic    heterocycle)-thio, (xix) amino which may have 1 or 2 substituent(s)    selected from the group consisting of (a) C₁₋₆ alkyl, (b) C₁₋₆    alkoxy-carbonyl, (c) optionally halogenated C₁₋₆ alkyl-carbonyl, (d)    C₆₋₁₀ aryl-carbonyl, (e) thienylcarbonyl, (f) C₁₋₆ alkylthio-C₁₋₆    alkyl-carbonyl, (g) mono- or di-C₁₋₆ alkyl-carbamoyl, (h) C₁₋₆    alkylsulfonyl, (i) C₆₋₁₀ arylsulfonyl, (j)    di-C₁₋₆alkylphosphono, (k) di-C₁₋₆alkylthiophosphono and (1) C₆₋₁₀    aryl-carbamoyl, (xx) phthalimido, (xxi) C₁₋₆    alkylsulfonyloxy, (xxii) 5- or 6-membered aromatic heterocyclic    group, (xxiii) phosphono which may have C₁₋₆ alkyl, (xxiv) 5- to    7-membered saturated cyclic amino which may have 1 or 2    substituent(s) selected from the group consisting of (a) C₇₋₁₂    aralkyl, (b) optionally halogenated C₆₋₁₀ aryl and (c) hydroxy    and (xxv) (5- to 7-membered cyclic amino)-carbonyl,-   (3) C₁₋₆ alkenyl which may have carboxy or C₁₋₆ alkoxy-carbonyl,-   (4) C₆₋₁₀ aryl which may have C₁₋₆ alkoxy,-   (5) C₁₋₆ alkoxy which may have substituents selected from the group    consisting of C₁₋₆ alkoxy, C₁₋₆ alkoxy-carbonyl, phthalimido,    di-C₁₋₆ alkylsulfonamido and di-C₁₋₆ alkylaminomethylenesulfonamido,-   (6) C₆₋₁₀ aryloxy which may have C₁₋₆ alkylthio,-   (7) C₇₋₁₂ aralkyloxy,-   (8) C₁₋₆ alkylthio which may have substituents selected from the    group consisting of mono- or di-C₁₋₆ alkylamino, carboxy, carbamoyl    and C₁₋₆ alkoxy-carbonyl,-   (9) C₁₋₆ alkylsulfinyl which may have substituents selected from the    group consisting of mono- or di-C₁₋₆ alkylamino, carboxy, carbamoyl    and C₁₋₆ alkoxy-carbonyl,-   (10) C₁₋₆alkylsulfonyl which may have substituents selected from the    group consisting of mono- or di-C₁₋₆ alkylamino, carboxy and C₁₋₆    alkoxy-carbonyl,-   (11) C₆₋₁₀ arylthio which may have substituents selected from the    group consisting of halogen atom, C₁₋₆ alkyl and C₁₋₆    alkoxy-carbonyl,-   (12) C₆₋₁₀ arylsulfinyl which may have C₁₋₆ alkyl,-   (13) C₆₋₁₀ arylsulfonyl which may have C₁₋₆ alkyl,-   (14) carboxy,-   (15) C₁₋₆ alkoxy-carbonyl,-   (16) C₇₋₁₂ aralkylthio,-   (17) C₇₋₁₂ aralkylsulfinyl,-   (18) C₇₋₁₂ aralkylsulfonyl,-   (19) amino which may have 1 or 2 substituent(s) selected from the    group consisting of C₁₋₆ alkyl, C₇₋₁₂ aralkyl, C₁₋₆ alkoxy-C₁₋₆    alkyl, C₁₋₆ alkoxy-carbonyl, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl,    carboxy-C₁₋₆ alkyl, C₁₋₆ alkyl-carbonyl, C₆₋₁₀ aryl-carbonyl, C₃₋₆    cycloalkyl-carbonyl, thienylcarbonyl, furylcarbonyl and mono- or    di-C₁₋₆ alkylamino-carbonyl,-   (20) 5- to 7-membered saturated cyclic amino which may have    substituents selected from the group consisting of (i) optionally    halogenated C₆₋₁₀ aryl, (ii) C₇₋₁₂ aralkyl, (iii) hydroxy, (iv) C₁₋₆    alkyl which may have C₁₋₆ alkoxy-carbonyl or carboxy, (v) oxo, (vi)    C₁₋₆ alkyl-carbonyl, (vii) C₆₋₁₀ aryl-carbonyl and (viii) C₁₋₆    alkoxy-carbonyl,-   (21) carbamoyl which may have substituents selected from the group    consisting of (i) C₁₋₆ alkyl which may have substituents selected    from the group consisting of halogen atom, C₁₋₆ alkoxy, amino, C₁₋₆    alkoxy-carboxamido and hydroxy, (ii) C₇₋₁₂ aralkyl and (iii) mono-    or di-C₁₋₆ alkylamino-carbonyl,-   (22) (5- to 7-membered cyclic amino)-carbonyl,-   (23) 5- or 6-membered aromatic heterocyclic group which may have    C₁₋₆ alkyl,-   (24) cyano,-   (25) (5- to 10-membered aromatic heterocyclic group)-thio which may    have C₁₋₆ alkyl,-   (26) C₁₋₆ alkylcarbonyl and-   (27) oxo. The “pyridyl” may be N-oxidized.

And also, preferable examples of R² are pyridazinyl or pyrazinyl, eachof which may have substituents selected from the group consisting of (1)C₁₋₆ alkylthio, (2) C₁₋₆ alkylsulfinyl, (3) C₁₋₆ alkyl sulfonyl and (4)amino which may have 1 or 2 C₁₋₆ alkyl (s) which may have C₁₋₆alkoxy-carbonyl or carboxy, and the like.

And also, preferable examples of R² are furyl, thienyl, pyrrolyl,quinolyl, pyrazinyl, pyrimidinyl, indolyl, tetrahydroquinolyl orthiazolyl, each of which may have 1 or 2 substituent(s) selected fromthe group consisting of (1) C₁₋₆ alkyl, (2) amino which may havesubstituent(s) selected from the group consisting of C₁₋₆ alkyl, C₁₋₆alkoxy-carbonyl, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl and carboxy-C₁₋₆ alkyl,(3) C₁₋₆ alkylsulfonyl and (4) mono- or di-C₁₋₆ alkylamino-C₁₋₆alkylthio, and the like.

More preferable examples of R² are pyridyl, furyl, thienyl, pyrrolyl,quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl,tetrahydroquinolyl or thiazolyl (preferably pyridyl, more preferably 2-or 4-pyridyl), each of which has 1 to 3 substituent(s) selected from thegroup consisting of (1) C₁₋₆ alkyl which may have substituents selectedfrom the group consisting of C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkoxy,carboxy-C₁₋₆ alkoxy, carboxy, C₁₋₆ alkoxy-carbonyl and C₁₋₆alkylsulfonyloxy, (2) C₁₋₆ alkenyl which may have carboxy or C₁₋₆alkoxy-carbonyl, (3) C₁₋₆ alkylthio which may have mono- or di-C₁₋₆alkylamino or C₁₋₆ alkoxy-carbonyl, (4) C₁₋₆ alkylsulfinyl which mayhave mono- or di-C₁₋₆ alkylamino, (5) C₁₋₆ alkylsulfonyl which may havemono- or di-C₁₋₆ alkylamino, (6) C₇₋₁₂ aralkylthio, (7) C₇₋₁₂aralkylsulfinyl, (8) C₇₋₁₂ aralkylsulfonyl, (9) carbamoyl which may havesubstituents selected from the group consisting of (i) C₁₋₆ alkyl whichmay have substituents selected from the group consisting of halogenatom, C₁₋₆ alkoxy and amino, (ii) C₇₋₁₂ aralkyl and (iii) mono- ordi-C₁₋₆ alkylamino-carbonyl and (10) (5- to 7-membered cyclicamino)-carbonyl, and the like. The “pyridyl” may be N-oxidized.

The most preferable examples of R² are pyridyl (preferably 2- or4-pyridyl) which has 1 or 2 substituent(s) selected from the groupconsisting of (1) C₁₋₆ alkyl which may have carboxy and/or hydroxy and(2) C₁₋₆ alkylsulfonyl, and the like.

Preferable substituted position is 5-, 6- or 7-position.

Examples of Compound (I) are (1) the compound wherein R¹ is a halogenatom, hydroxy, nitro, optionally halogenated alkyl, alkoxy which mayhave substituents, acyl or amino which may have substituents; R² ispyridyl, furyl, thienyl, pyrrolyl, quinolyl, pyrazinyl, pyrimidinyl,pyridazinyl, indolyl, tetrahydroquinolyl or thiazolyl, each of which hassubstituents respectively; n is 1 or 2, (2) the compound wherein R¹ is ahydrogen atom; R² is pyridyl, furyl, thienyl, pyrrolyl, quinolyl,pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, tetrahydroquinolyl orthiazolyl, each of which has substituents respectively, and the like.

The example of Compound (I) is a compound represented by the formula:

wherein R¹ and R² have the same meaning described above, or a saltthereof. Preferably R¹ is a hydrogen atom, a halogen atom, optionallyhalogenated alkyl or optionally halogenated alkoxy, and the like.

Especially, the most preferable compounds of this invention are, forexample,

-   3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propionic acid,-   3-[6-(7-chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-4-methyl-2-pyridyl]propionic    acid,-   3-[2-(7-chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]pr opionic    acid,-   3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propionic acid,-   3-[2-methyl-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]pr opionic    acid,-   3-[2-(7-chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-6-methyl-4-pyridyl]propionic    acid or salts thereof.

Examples of a salt of Compound (I) and intermediates thereof are metalsalts, ammonium salts, salts with organic bases, salts with inorganicacids, salts with organic acids, salts with basic or acidic amino acids,and the like. Suitable examples of metal salts are alkali metal saltssuch as sodium salt, potassium salt; alkali-earth metal salts such ascalcium salt, magnesium salt, barium salt; aluminum salts; and the like.Suitable examples of the salt with organic bases are salts withtrimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine,ethanolamine, diethanolamine, triethanolamine, cyclohexylamine,dicyclohexylamine, N,N-dibenzylethylenediamine, and the like. Suitableexamples of the salt with inorganic acids are salts with hydrochloricacid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, andthe like. Suitable examples of the salt with organic acids are saltswith formic acid, acetic acid, trifluoroacetic acid, phthalic acid,fumalic acid, oxalic acid, tartaric acid, maleic acid, citric acid,succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, and the like. Suitable examples of the salt withbasic amino acid are salts with arginine, lysine, ornithine, and thelike. Suitable examples of the salt with acidic amino acids are saltswith aspartic acid, glutamic acid, and the like.

Among them, pharmaceutically acceptable salts are preferable. And in thecase of the compound having an acidic functional group, examples of thesalt are in organic salts such as alkali metal salts (e.g., sodium salt,potassium salt, and the like), alkali-earth metal salts (e.g., calciumsalt, magnesium salt, barium salt, and the like); ammonium salt; and thelike. And in the case of the compound having a basic functional group,examples of the salt are salts with inorganic acids such as hydrobromicacid, nitric acid, sulfuric acid, phosphoric acid; and salts withorganic acids such as acetic acid, phthalic acid, fumalic acid, tartaricacid, maleic acid, citric acid, succinic acid, methanesulfonic acid,p-toluenesulfonic acid, and the like.

Compound (I) may be a hydrate or a non-hydrate. The hydrate isexemplified by semihydrate, monohydrate, sesquihydrate and dihydrate.

When compound (I) is obtained as a mixture of optically activesubstances (racemic body), it can be resolved into the objective (R)-and (S)-forms by per se known optical resolution techniques.

A prodrug of Compound (I) is a compound which is converted into Compound(I) under a physiological condition as a result of a reaction with anenzyme or gastric acid, thus a compound undergoing enzymatic oxidation,reduction or hydrolysis to form Compound (I) and a compound hydrolyzedby gastric acid, etc. to form Compound (I). A prodrug of Compound (I)may for example be a compound obtained by subjecting amino group inCompound (I) to acylation, alkylation or phosphorylation (e.g., acompound obtained by subjecting amino group in Compound (I) toeicosanoylation, alanylation, pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylationand tert-butylation, and the like); a compound obtained by subjectinghydroxy group in Compound (I) to acylation, alkylation, phosphorylationor boration (e.g., a compound obtained by subjecting hydroxy group inCompound (I) to acetylation, palmitoylation, propanoylation,pivaloylation, succinylation, fumarylation, alanylation,dimethylaminomethylcarbonylation, and the like); a compound obtained bysubjecting carboxy group in Compound (I) to esterification or amidation(e.g., a compound obtained by subjecting carboxy group in Compound (I)to ethylesterification, phenylesterification,carboxymethylesterification, dimethylaminomethylesterification,pivaloyloxymethylesterification, ethoxycarbonyloxyethylesterification,phthalidylesterification,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterification,cyclohexyloxycarbonylethylesterification and methylamidation, and thelike) and the like. Any of these compounds can be produced from Compound(I) by a method known per se.

A prodrug of Compound (I) may also be one which is converted intoCompound (I) under a physiological condition, such as those described in“IYAKUHIN NO KAIHATSU (Development of Pharmaceuticals)”, Vol. 7, Designof Molecules, p. 163-198, Published by HIROKAWA SHOTEN (1990).

The production method of Compound (I) is described below.

Compound (I) can be produced by the method represented by Scheme 1 orits analogous methods.

Each symbol in Scheme 1 described below has the same meaning describedabove. In the scheme, the compound may contain salt forms, and examplesof the salts are the same as salts of Compound (I), and the like.

Compound (I) can be produced by reacting Compound (II) and Compound(III).

In Compound (II), L is a hydrogen atom or a leaving group. Examples ofthe leaving group are alkyl and the like.

This reaction may be performed in the presence of base.

The amount of Compound (III) is about 0.4 to 2 moles, preferably about0.8 to 1.2 moles per 1 mole of Compound (II).

The amount of base is about 1 to 2.5 moles, preferably about 0.8 to 1.5moles per 1 mole of Compound (II).

Examples of the “base” are basic salts such as sodium carbonate,potassium carbonate, cesium carbonate, and the like; inorganic basessuch as sodium hydroxide, potassium hydroxide, and the like; aromaticamines such as pyridine, lutidine, and the like; tertiary amines such astriethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine, and the like; metal hydridessuch as sodium hydride, potassium hydride and the like; metal amidessuch as sodium amide, lithium diisopropyl amide, lithiumhexamethyldisilazide, and the like; metal alkoxides such as sodiummethoxide, sodium ethoxide, potassium tert-butoxide, and the like; andthe like.

It is advantageous to perform this reaction without using solvent or inthe solvent inert to this reaction. The solvent is not limited as longas the reaction is proceeded. Examples of the solvent are aromaticamines, halgenated hydrocarbons, aliphatic hydrocarbons, aromatichydrocarbons, ethers, amides, or mixture of 2 or more thereof. Amongthem, pyridine and toluene and the like are preferable. And when thereaction is performed in pyridine, base is not always necessary.

The reaction temperature is normally about 100 to 150° C., preferably120 to 130° C. The reaction time is normally about 3 hours to 72 hours,preferably about 8 to 24 hours at the boiling point of the solvent used.

This reaction is performed under reflux at the boiling point of thesolvent used.

Compound (II) can be used as it is when it can be commerciallyavailable. And it can be produced in accordance with the known methodsper se or analogous methods thereof. For example, Compound (II) can beobtained from anthrailic acid derivatives corresponding to Compound (II)by the known method (e.g., Journal of organic Chemistry, Vol. 18, pp.1380, 1953, etc.) and from salicylic acid derivatives corresponding toCompound (II) by the known method (e.g., Journal of organic Chemistry,Vol. 31, pp. 3980, 1966, etc.).

Compound (III) can be used as it is when it can be commerciallyavailable. And it can be produced in accordance with the known methodsper se or analogous methods thereof. For example, Compound (III),wherein R² is pyridyl which may have substituents, can be obtained frompyridine derivatives corresponding to Compound (III) by the known method(e.g., Journal of organic Chemistry, Vol. 48, pp. 1375, 1983; Synthesis,Vol. 316, pp. 316, 1983, etc.).

In the reaction described above, a starting compound having an amino,carboxy or hydroxy as its substituent may be present as a compound inwhich a protective group employed ordinarily in a peptide chemistry hasbeen introduced into such a substituent, and an intended compound can beobtained by deprotection if necessary after the reaction.

A protective group for an amino may for example be a formyl or eachoptionally substituted C₁₋₆ alkyl-carbonyl (e.g., acetyl, propionyl, andthe like), phenylcarbonyl, C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl,ethoxycarbonyl, and the like), phenyloxycarbonyl, C₇₋₁₀aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, and the like), trityl,phthaloyl and the like. Its substituent may for example be a halogenatom (e.g., fluorine, chlorine, bromine, iodine, and the like), C₁₋₆alkyl-carbonyl (e.g., acetyl, propionyl, valeryl, and the like), nitroand the like, and the number of the substituents may be 1 to 3.

A protective group for a carboxy may for example be each optionallysubstituted C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, 2-trimethyl, and the like), phenyl, trityl, silyl and thelike. Its substituent may for example be a halogen atom (for example,fluorine, chlorine, bromine, iodine, and the like), formyl, C₁₋₆alkyl-carbonyl (e.g., acetyl, propionyl, butylcarbonyl, and the like),nitro, C₁₋₆ alkyl (e.g., methyl, ethyl, tert-butyl, and the like) andC₆₋₁₀ aryl (e.g., phenyl, naphthyl, and the like), and the number of thesubstituents may be 1 to 3.

A protective group for a hydroxy may for example be each optionallysubstituted C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, and the like), phenyl, C₇₋₁₁ aralkyl (e.g., benzyl, and thelike), formyl, C₁₋₆ alkyl-carbonyl (e.g., acetyl, propionyl, and thelike), phenyloxycarbonyl, C₇₋₁₁ aralkyloxy-carbonyl (e.g.,benzyloxycarbonyl, and the like), tetrahydropyranyl, tetrahydrofuranyl,silyl and the like. Its substituent may for example be a halogen atom(e.g., fluorine, chlorine, bromine, iodine, and the like), C₁₋₆ alkyl(e.g., methyl, ethyl, tert-butyl, and the like), C₇₋₁₁ aralkyl (e.g.,benzyl, and the like), C₆₋₁₀ aryl (e.g., phenyl, naphthyl, and thelike), nitro, and the like, and the number of the substituents may be 1to 4.

A deprotection method may be a method known per se such as a treatmentwith an acid, base, UV, hydrazine, phenylhydrazine, sodiumN-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetateand the like, as well as a reduction.

In any case, a deprotection, acylation, alkylation, hydrogenation,oxidation, reduction, carbon chain elongation and substituent exchangereaction are further employed if necessary alone or in combination witheach other to synthesize Compound (I). These reactions may employ themethods described for example in SHINJIKKENKAGAKUKOZA, Vols. 14 and 15,1977 (MARUZEN) and the like.

Examples of the “aromatic amines” described above are pyridine,lutidine, quinoline, and the like.

Examples of the “halogenated hydrocarbons” described above aredichloromethane, chloroform, 1,2-dichloroethane, and the like.

Examples of the “aliphatic hydrocarbons” described above are hexane,pentane, cyclohexane, and the like.

Examples of the “aromatic hydrocarbons” described above are benzene,toluene, xylene, chlorobenzene, and the like.

Examples of the “ethers” described above are diethyl ether, diisopropylether, diphenyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane,and the like.

Examples of the “amides” described above are N,N-dimethylformamide,N,N-dimethylacetamide, hexamethylphosphoric triamide, and the like.

When an objective product is obtained in a free form by a reactiondescribed above, then it may be converted in accordance with an ordinarymethod into a salt, and when it is obtained as a salt then it may beconverted in accordance with an ordinary method into a free form oranother salt. Compound (I) thus obtained can be isolated and purifiedfrom a reaction solution by a known method such as a partition,concentration, solvent extraction, fraction distillation,crystallization, recrystallization, chromatography and the like.

When Compound (I) is present as a configuration isomer, diastereomer,conformer and the like, then it can be isolated if desired by aseparation or purification procedure described above. When Compound (I)is present as a racemate, it can be resolved into S form and R form byan ordinary optical resolution method.

When Compound (I) has its stereoisomers, then individual isomers or amixture thereof may also encompassed in this invention.

Compound (I) of this invention has an excellent inhibitory action onapoptosis (e.g., inhibitory action on apoptosis and heart muscle cells,and the like) to an animal, especially to a mammal (e.g., human, monkey,dog, cat, rabbit, guinea pig, rat, mouse, and the like) and a lowtoxicity. Furthermore, Compound (I) of this invention has an ability tobind macrophage migration-inhibitory factor (MIF) and inhibits theapoptosis based on oxidation-stress, removal of serum, lack of growthfactor, HMG-CoA reductase inhibitor, anti-cancer drug, NO, amyloid βprotein, and the like. For example, the apoptosis derived from severalfactors is observed as an elimination of heart muscle cells from heartmuscle, which gives a malignant effect on heart function. Therefore, thecompound having apoptosis inhibitory effect on heart muscle cells canprevent the malignant effect on heart function derived from theelimination of heart muscle cells. And Compound (I) of this inventionalso has an inhibitory effect on the proliferation of tumor and thearterialization.

On the basis of that, Compound (I) is useful as a safe pharmaceuticaland can be used as a pharmaceutical for preventing and/or treating heartdisease [e.g., cardiomyopathy (e.g., congestive cardiomyopathy,hypertrophic obstructive cardiomyopathy, hypertrophic cardiomyopathy,idiopathic cardiomyopathy, constrictive cardiomyopathy, diabeticcardiomyopathy, and the like), heart failure (e.g., chronic heartfailure, chronic congestive heart failure, acute heart failure, cardiacdecompensation, left cardic failure, right heart failure, congestiveheart failure, acute congestive heart failure, metabolic heart failure,congestive heart failure, high output heart failure, low output heartfailure, intractable heart failure, muscle infarction prognosis failure,and the like), angina pectoris, myocardial infarction, and the like],nervous degenerative disease [e.g., Parkinson's disease, Alzheimerdisease, triplet repeat disease (e.g., Huntington's chorea,spinocerebellar imbalance type-I, Machado-Joseph disease, dentate rubropallido luysian atrophy, and the like), prion disease (e.g.,Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, and thelike), amyotrophic lateral sclerosis (ALS), cerebellum degeneration,retinitis pigmentosa, and the like], cerebrovascular disease (e.g.,cerebral infarction, and the like), central nervous infectious disease(e.g., HIV encephalitis, bacterial meningitis, and the like),traumatorathy (e.g., spine damage, cerebral damage, and the like),demyelinating disease (e.g., multiple scleroma, and the like), bone andarticular disease (e.g., osteoporosis, osteoarthritis, rheumatism, andthe like), kidney disease (e.g., ischemic acute renal failure, hemolyticuremic syndrome, acute tubulorrhexis, hydronephrosis, glomerularnephritis, diabetic nephropathy, transplantation rejection kidney, andthe like), liver disease (e.g., viral hepatitis, alcoholic hepatitis,and the like), osteomyelodysplasia (e.g., aplastic anemia, and thelike), AIDS, arteriosclerosis, diabetes, pulmonary hypertension, sepsis,septicaemia, inflammatory bowel disease, autoimmune disease (e.g.,systematic lupus erythematosus, atopic dermatitis, and the like),transplanted organ disorder in rejection, cancer (e.g., colon cancer,breast cancer, lung cancer, prostatic cancer, esophageal carcinoma,stomach cancer, liver cancer, carcinoma of biliary tract, lienal cancer,renal cancer, bladder cancer, uterine cancer, testoid cancer, thyroidcancer, pancreatic cancer, brain tumor, hematic cancer, and the like),and the like.

When Compound (I) is used as a pharmaceutical for preventing and/ortreating diseases described above, the administration route may be oralor parenteral in accordance with the known method per se. And it may beadministered orally as a solid preparation such as tablet, capsule,granule, powder, and the like or parenterally as an intravenous,subcutaneous or intramuscular injection formulation, a suppository or atroche. And it may be administered hypoglossaly, subcutaneously orintramuscularly as a sustained formulation such as troche, microcapsule,and the like

The dosage of Compound (I) may vary depending on administration target,administration route, condition, and the like, and is not limitedespecially, a daily dose in an adult having heart failure is usually0.001 to 10 mg/kg, preferably 0.001 to 0.2 mg/kg, more preferably 0.001to 0.02 mg/kg, which is given once to in three portions a day.

The amount of Compound (I) in a pharmaceutical of this invention isusually about 0.01 to 100% by weight based on the entire pharmaceutical.

The pharmaceutically acceptable carriers include a wide variety oforganic or inorganic carrier materials conventionally used forpharmaceutical preparations, and are mixed, for example, as excipients,lubricants, binders, disintegrators in solid preparation; solvents,solubilizers, suspending agents, isotonizing agents, buffers andpainkillers in liquid preparation. If necessary, additives such aspreservatives, antioxidants, coloring agents, sweeteners, etc. can alsobe used.

Preferable examples of the excipient are lactose, sucrose, D-mannitol,starch, crystalline cellulose, light silicic anhydride, and the like.Preferable examples of the lubricant are magnesium stearate, calciumstearate, talc, colloidal silica, and the like. Preferable examples ofthe binder are crystalline cellulose, sucrose, D-mannitol, dextrin,hydroxypropylcellulose, hydroxypropylmethylcellulose,polyvinylpyrrolidone, and the like. Preferable examples of thedisintegrator are starch, carboxymethylcellulose, calciumcarboxymethylcellulose, sodium croscarmellose, sodium carboxymethylstarch, and the like. Preferable examples of the solvent are water forinjection, alcohol, propylene glycol, Macrogol, sesame oil, corn oil,and the like. Preferable examples of the solubilizer are polyethyleneglycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate, and the like. Preferable examples of the suspending agent aresurfactant such as stearyl triethanolamine, sodium laurylsulfate, laurylaminopropionic acid, lecithin, benzalconium chloride, benzetoniumchloride, glycerine monostearate, and the like; and hydrophilic polymerssuch as polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethylcellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, and the like. Preferable examples ofthe isotonizing agent are sodium chloride, glycerine, D-mannitol, andthe like. Preferable examples of the buffer are buffer such asphosphate, acetate, carbonate, citrate, and the like. Preferableexamples of the painkiller are benzyl alcohol, and the like. Preferableexamples of the preservative are p-hydroxybenzoic acid ester,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid,sorbic acid, and the like. Preferable examples of the antioxidant aresulfite, ascorbic acid, and the like.

An intravenous, subcutaneous or intramuscular injection formulation canbe produced by the adding suspending agents, solubilizers, stabilizers,isotonizing agents, preservatives to Compound (I) in accordance withknown method per se. The intravenous, subcutaneous or intramuscularinjection formulation can be converted to freeze-dried formulation. Whenthe compound of this invention is administered to human, it can beconverted as a pharmaceutical composition as it is or combining withpharmaceutically acceptable carriers, excipients, diluents andadministered orally or parenterally.

Examples of the pharmaceutical composition are oral drug (e.g., powder,granule, capsule, tablet), injection formulation, drop, externalpreparation (e.g., nose drop, endermism, and the like), suppository(e.g., rectum suppository, vagina suppository), and the like.

These pharmaceutical preparations can be produced by a method known perse which is employed usually in a pharmaceutical process.

Compound (I) can be formulated with dispersant (e.g., Tween 80 (ATLASPOWDER, USA), HCO60 (NIKKO CHEMICALS), polyethylene glycol,carboxymethyl cellulose, sodium alginate, and the like), preservative(e.g., methylparabene, propylparabene, benzyl alcohol, and the like),isotonicity agent (e.g., sodium chloride, mannitol, sorbitol, glucose,etc.), and the like into aqueous formulation for injection, ordissolved, suspended or emulsified in a vegetable oil such as olive oil,sesame oil, cottonseed oil and corn oil, etc. and in propylene glycol,etc. to form an oily formulation, whereby producing an injectionformulation.

In order to obtain an oral dosage form, a method known per se isemployed to compress compound (I) for example with excipient (e.g.,lactose, sugar, starch, and the like), disintegrator (e.g., starch,calcium carbonate, etc.), binder (e.g., starch, gum arabic,carboxymethyl cellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose,and the like) or lubricant (e.g., talc, magnesium stearate, polyethyleneglycol 6000, and the like), and the like into a desired shape, which isthen subjected to taste masking, covered with enteric coating orimparted with a sustained release performance if necessary by means of acoating method known per se, whereby obtaining an oral dosage form.Examples of the coating are hydroxypropylmethyl cellulose, ethylcellulose, hydroxymethyl cellulose, hydroxypropyl cellulose,polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetatephthalate, hydroxypropylmethyl cellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (Rohm, German, methacrylic/acrylicacid copolymer) and colorant (e.g., iron oxide red, titanium dioxide,etc.). When Compound (I) is produced as an enteric coating formulation,the intermediate phase can be located between enteric coating phase anddrug containing phase in order to isolate the two phases.

In order to obtain external preparation, a method known per se isemployed to convert Compound (I) or salt thereof into a solid,semi-solid or liquid external preparation. For example, the solidexternal preparation can be produced by Compound (I) or salt thereof asit is or by combining Compound (I) with excipient (e.g., glycol,mannitol, starch, micro crystalline cellulose, and the like), thickener(e.g., natural gum, cellulose derivatives, acrylic acid polymer, and thelike), and the like. The liquid external preparation such as oily oraqueous suspension can be produced in accordance with the method forproducing the injection formulation. Examples of the semi-solid externalpreparation are aqueous or oily gel, or ointment. And each of them canbe combined with pH adjusting agent (e.g., carbonic acid, phosphoricacid, citric acid, hydrochloric acid, sodium hydroxide, and the like),antiseptics (e.g., p-hydroxybenzoic acid ester, chlorobutanol,benzalconium chloride, and the like), and the like.

In order to obtain for example suppository, a method known per se isemployed to convert Compound (I) into an oily or aqueous solid,semi-solid or liquid suppository. The oily base employed in acomposition described above may for example be a higher fatty acidglyceride [e.g., cocoa butter, UITEPSOL (DYNAMITE NOVEL, Germany),etc.], a medium fatty acid [e.g., MIGRIOL (DYNAMITE NOVEL, Germany),etc.], or vegetable oil (e.g., sesame oil, soybean oil, cottonseed oil,and the like), and the like. The aqueous base may for example bepolyethylene glycol and propylene glycol, and the aqueous gel base mayfor example be natural gums, cellulose derivatives, vinyl polymers andacrylic acid polymers, and the like.

Examples of the drug which can be administered together with Compound(I) are described below. Each of the drugs may be administered orally orparenterally (e.g., nose drop, injection formulation, suppository, andthe like). And each of the drugs can be blended into one formulation.And each of the drugs can be formulated by combining withpharmacologically acceptable carriers, excipients, binders, diluents,and the like respectively and administered respectively orsimultaneously. In case that each of the drugs is formulatedrespectively, each of the drugs can be administered to the same targetsimultaneously or separately as well as they can be administered bymixing them and diluents when they are used.

Examples of the drug obtaining synergism effects together with Compound(I) are inotropic agents (e.g., cardiac glycosides such as digoxin, andthe like; β-agonist such as dopamine, dobutamine, and the like;phosphodiesterase inhibitor such as amrinone, milrinone, and the like);anti heart failure drug (e.g., class I of anti heart failure drug suchas disopyramide, lidocaine, procainamide, and the like; class III ofanti heart failure drug such as amiodarone, sotalol and the like;β-blocker such as propranolol, and the like); vasodilator (e.g.,angiotensin converting enzyme inhibitor such as captopril, enalapril,and the like; nitrous acid drug such as nitroprusside, isosorbidedinitrate, and the like; calcium receptor inhibitor such as verapamil,diltiazem, nicardipine, nifedipine, and the like; angiotensin IIreceptor inhibitor such as losartan, candesartan, and the like);diuretic (e.g., loop diuretic such as furosemide, bumetanide, and thelike; thiazide diuretic such as chlorothiazide, bendrofluazide, and thelike; potassium sparing diuretic such as amiloride, spironolactone, andthe like); and the like.

And when Compound (I) is used together with HMG-CoA reductase inhibitor(e.g., simvastatin, atorvastatin, and the like), fibrate-type drug forhyperlipemia (e.g., gemfibrozil, and the like), anti cancer drug (e.g.,ifosfamide, UFT, adriamycin, doxorubicin, peplomycin, cisplatin,cyclophosphamide, 5-FU, methotrexate, mitomycin C, mitoxantrone, and thelike), and the like, the side-effect derived from HMG-CoA reductaseinhibitor, fibrate-type drug for hyperlipemia, anti cancer drug and thelike, which gives wounds to normal cells, can be reduced.

This invention will be now further described specifically with referenceto the following Reference Examples, Examples, Formulation examples andExperimental Examples, which are however not intended to limit the scopeof the present invention.

In the following Reference Examples, “%” means % by weight unlessotherwise specified. ¹H-NMR spectra were measured by Bruker AVANCEDPX-300 (300 MHz) spectrometer with tetramethyl silane as the internalstandard. All 5 values are expressed in ppm.

The abbreviations as used herein have the following meanings.

-   s: singlet-   d: doublet-   dd: double doublet-   t: triplet-   tt: triple triplet-   q: quartet-   m: multiplet-   br: broad-   J: coupling constant-   Hz: Hertz-   DMF: N,N-dimethylformamide-   CDCl₃: deuterated chloroform-   DMSO-d₆: dimethylsulfoxide-d₆-   IR: infrared absorption spectrum-   WSC: 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride-   HOBt: 1-hydroxybenzotriazole

The “room temperature” usually means about 10° C. to 35° C., however,that is not limited strictly.

EXAMPLES Example 1

2-(2-Furyl)-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (1.01 g, 6.0 mmol), 2-furonitrile(0.57 g, 6.0 mmol), triethylamine (1.5 ml, 10.7 mmol) and toluene (20ml) was refluxed for 24 hrs. After cooling, the precipitated crystalswere collected by filtration and recrystallized from hexane-ethanol togive the titled compound (0.26 g, 19%)

mp. 170.0-171.5° C.

IR (KBr): 3132, 3072, 1653, 1572, 1508, 1456, 1296, 1271, 1101, 1014,860, 744, 592 cm⁻¹.

¹H-NMR (CDCl₃) δ: 6.65 (1H, dd, J=1.8, 3.5 Hz), 7.48-7.71 (5H, m), 6.51(1H, dd, J=1.5, 5.0 Hz).

Elemental Analysis for C₁₂H₇NO₂S

Calcd. C, 62.87; H, 3.08; N, 6.11.

Found C, 62.84; H, 2.92; N; 6.23.

Example 2

2-(2-Thienyl)-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (1.60 g, 9.5 mmol),2-thiophenecarboxylic acid (1.04 g, 9.5 mmol), triethylamine (2.0 ml,14.3 mmol) and toluene (2 ml) was refluxed for 12 hrs. After cooling,the precipitated crystals were collected by filtration andrecrystallized from methanol-ether to give the titled compound (1.71 g,73%).

mp. 157.7-158.2° C.

IR (KBr): 3084, 1649, 1521, 1500, 1408, 1292, 1248, 1099, 841, 760, 731cm⁻¹.

¹H-NMR (CDCl₃) δ: 7.21 (1H, m), 7.49 (1H, m), 7.58-7.73 (3H, m), 7.96(1H, m), 8.50 (1H, m).

Elemental Analysis for C₁₂H₇NOS₂

Calcd. C, 58.75; H, 2.88; N, 5.71.

Found C, 58.74; H, 2.67; N, 5.90.

Example 3

2-(2-Quinolinyl)-4H-1,3-benzothiazine-4-one

The titled compound was obtained by the reaction of methylthiosalicylate (1.00 g, 5.9 mmol) and 2-quinolinecarbonitrile (0.95 g,6.2 mmol) in accordance with the method described in Example 1 (1.54 g,89%).

mp. 262.7-263.4° C. (recrystallized from chloroform)

IR (KBr): 3055, 1651, 1593, 1570, 1529, 1440, 1292, 1097, 929, 837, 740cm⁻¹.

¹H-NMR (CDCl₃) δ: 7.63-7.70 (4H, m), 7.81 (1H, m), 7.90 (1H, d), 8.23(1H, d), 8.34 (1H, d), 8.58-8.62 (2H, m).

Elemental Analysis for C₁₇H₁₀N₂OS

Calcd. C, 70.33; H, 3.47; N, 9.65.

Found C, 70.27; H, 3.48; N, 9.80.

Example 4

2-(3-Quinolinyl)-4H-1,3-benzothiazine-4-one

The titled compound was obtained by the reaction of methylthiosalicylate (1.00 g, 5.9 mmol) and 3-quinolinecarbonitrile (0.92 g,6.0 mmol) in accordance with the method described in Example 1 (0.30 g,17%).

mp. 216.0-217.0° C. (recrystallized from chloroform-hexane)

IR (KBr): 3045, 1657, 1591, 1572, 1518, 1458, 1439, 1292, 1236, 1097,920, 738 cm⁻¹.

¹H-NMR (CDCl₃) δ: 7.59-7.73 (4H, m), 7.87 (1H, m), 8.00 (1H, d, J=8.0Hz), 8.20 (1H, d, J=8.4 Hz), 8.58 (1H, dd, J=1.3, 7.6 Hz), 9.02 (1H, d,J=2.1 Hz), 9.64 (1H, d, J=2.1 Hz)

Elemental Analysis for C₁₇H₁₀N₂OS

Calcd. C, 70.33; H, 3.47; N, 9.65.

Found C, 70.36; H, 3.44; N, 9.78.

Reference Example 1

2-Cyano-6-methylpyridine

2-Mehtylpyridinium-N-oxide (2.00 g, 18.3 mmol) was dissolved innitroethane (10 ml). Trimethylsilylcyanide (2.7 ml, 20.2 mmol) anddimethylcarbamyl chloride (1.7 ml, 18.5 mmol) were added thereto and themixture was stirred at room temperature for 22 hrs. After evaporation ofthe solvent, the residue was combined with ethyl acetate and saturatedaqueous sodium hydrogen carbonate solution and stirred. The water layerwas extracted with ethyl acetate once. The combined organic layer waswashed with saturated brine once, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The obtained crystals werewashed with isopropyl ether and dried to give the titled compound (0.61g, 28%).

¹H-NMR (CDCl₃) δ: 2.62 (3H, s), 7.38 (1H, d, J=7.9 Hz), 7.52 (1H, d,J=7.8 Hz), 7.71 (1H, t, J=7.8 Hz).

Example 5

tert-Butyl

3-[6-(7-chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]pr opanoate

4-Chloro-2-mercaptobenzoic acid (2.60 g, 13.7 mmol) and tert-butyl3-(6-cyano-2-pyridyl)propanoate (1.60 g, 6.9 mmol) were dissolved inpyridine (15 ml), and the mixture was refluxed for 13 hrs. The reactionmixture was concentrated under reduced pressure, subjected to silica gelcolumn chromatography and eluted with hexane-ethyl acetate (3:1, v/v) togive the titled compound (1.42 g, 51%).

mp. 167.9-168.2° C.

IR (KBr): 2976, 2932, 1726, 1678, 1585, 1570, 1535, 1379, 1271, 1149,1093, 995, 814, 733 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 2.87 (2H, t, J=7.2 Hz), 3.20 (2H, t,J=7.2 Hz), 7.43 (1H, d, J=7.3 Hz), 7.56 (1H, dd, J=2.0, 8.5 Hz), 7.62(1H, d, J=2.0 Hz), 7.80 (1H, dd, J=7.3, 7.5 Hz), 8.34 (1H, d, J=7.5 Hz),8.47 (1H, d, J=8.5 Hz).

Elemental Analysis for C₂₀H₁₉N₂O₃SCl

Calcd. C, 59.62; H, 4.75; N, 6.95.

Found C, 59.65; H, 4.96; N, 7.15.

Example 6

3-[6-(7-Chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]pr opionic acid

A mixture of tert-butyl3-[6-(7-chloro-4-oxo-4H-1,3-banzothiazin-2-yl)-2-pyridyl]pr opanoateobtained in Example 5 (0.60 g, 1.5 mmol) and trifluoroacetic acid (5.0ml) was stirred at 0° C. for 2 hrs. The reaction mixture wasconcentrated under reduced pressure. Diisopropyl ether was added theretoto precipitate crystals, which were collected by filtration and dried togive the titled compound (0.49 g, 96%)

mp. 224.4-224.7° C.

IR (KBr): 3051, 2922, 1709, 1664, 1585, 1566, 1529, 1379, 1261, 1230,1095, 846, 804 cm⁻¹.

¹H-NMR (DMSO-d₆) δ: 2.80 (2H, t, J=7.1 Hz), 3.13 (2H, t, J=7.1 Hz), 7.65(1H, d, J=7.7 Hz), 7.73 (1H, dd, J=2.0, 8.5 Hz), 8.00 (1H, m), 8.13-8.17(2H, m), 8.31 (1H, d, J=8.5 Hz), 12.20 (1H, br s).

Elemental Analysis for C₁₆H₁₁N₂O₃SCl·0.25H₂O

Calcd. C, 54.71; H, 3.30; N, 7.97.

Found C, 54.85; H, 3.14; N, 7.82.

Example 7

2-Pyrazinyl-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (1.68 g, 10.0 mmol), cyanopyrazine(1.06 g, 10.1 mmol), triethylamine (2.10 ml, 15.1 mmol) and toluene(10.0 ml) was refluxed at 120° C. for 8 hrs. The solvent was evaporatedand the residue was recrystallized from dioxane-hexane to give thetitled compound (0.54 g, 22%) as crystals.

mp. 240.7-241.7° C.

IR(KBr):3069, 1668, 1574, 1537, 1464, 1439, 1404, 1280, 1267, 1255,1232, 1165, 1124, 1095, 1062, 1053, 1033, 1018, 939, 864, 825, 798, 760,744 cm⁻¹.

¹H-NMR(CDCl₃) δ: 7.61-7.75 (4H, m), 8.55-8.58 (1H, m), 8.70-8.72 (1H,m), 8.85 (1H, d, J=2.4 Hz), 9.72 (1H, d, J=1.3 Hz).

Elemental Analysis for C₁₂H₇N₃OS

Calcd. C, 59.74; H, 2.92; N, 17.42.

Found C, 59.47; H, 2.82; N, 17.21.

Example 8

2-(3-Methyl-2-pyridyl)-4H-1,3-benzothiazine-4-one

The titled compound was obtained by the reaction of methylthiosalicylate (1.68 g, 10.0 mmol) and 3-methyl-2-cyanopyridine (1.19 g,10.0 mmol) in accordance with the method described in Example 1 (0.09 g,4%).

mp. 149.9-151.6° C.

IR(KBr): 3061, 1664, 1574, 1537, 1440, 1413, 1404, 1386, 1321, 1302,1256, 1236, 1209, 1186, 1134, 1120, 1095, 1060, 1030, 1033, 999, 985,964, 931, 868, 825, 790, 763, 740 cm⁻¹.

¹H-NMR(CDCl₃) δ: 2.87 (3H, s), 7.39-7.42 (1H, m), 7.56-7.71 (4H, m),8.50-8.60 (2H, m).

Elemental Analysis for C₁₄H₁₀N₂OS

Calcd. C, 66.12; H, 3.96; N, 11.02.

Found C, 65.94; H, 3.92; N, 11.23.

Example 9

6-Chloro-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of 5-chloro-2-mercaptobenzoic acid (2.00 g, 10.6 mmol),2-cyanopyridine (1.10 g, 10.5 mmol) and pyridine (50.0 ml) was refluxedfor 9 hrs. After cooling, the precipitated crystals were collected byfiltration and recrystallized from hexane-chlorobenzene to give thetitled compound (0.78 g, 27%)

mp. 269.4-270.1° C.

IR(KBr): 3086, 3061, 1660, 1568, 1531, 1313, 1234, 945, 790 cm⁻¹.

¹H-NMR(CDCl₃+DMSO-d₆) δ: 7.57-7.70 (3H, m,), 7.95 (1H, m, 8.49-8.51 (2H,m), 8.75 (1H, m).

Elemental Analysis for C₁₃H₇N₂OSCl

Calcd. C, 56.83; H, 2.57; N, 10.20.

Found C, 56.95; H, 2.41; N, 10.31.

Example 10

7-Chloro-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of 4-chloro-2-mercaptobenzoic acid (6.00 g, 31.8 mmol),2-cyanopyridine (1.90 g, 17.7 mmol) and pyridine (50.0 ml) was refluxedfor 9 hrs as described in Example 9. After cooling, the precipitatedcrystals were collected by filtration and recrystallized fromhexane-chlorobenzene to give the titled compound (2.30 g, 48%)

mp. 245.3-245.6° C.

IR(KBr): 1666, 1589, 1564, 1535, 1458, 1429, 1379, 1302, 1273, 1234,1107, 1087, 860, 790, 740 cm⁻¹.

¹H-NMR(CDCl₃) δ: 7.54-7.60 (3H, m,), 7.92 (1H, m,), 8.47 (1H, d), 8.52(1H, d), 8.74 (1H, dd)

Elemental Analysis for C₁₃H₇N₂OSCl

Calcd. C, 56.83; H, 2.57; N, 10.20.

Found C, 56.82; H, 2.76; N, 10.07.

Example 11

6-Bromo-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one

5-Bromo-2-mercaptobenzoic acid (4.10 g, 17.6 mmol), 2-cyanopyridine(1.70 g, 16.3 mmol) and pyridine (50.0 ml) were refluxed for 9 hrs asdescribed in Example 9. After cooling, the precipitated crystals werecollected and recrystallized from hexane-chlorobenzene to give thetitled compound (2.40 g, 45%).

mp. 253.0-253.7° C.

IR(KBr): 3061, 1658, 1566, 1527, 1388, 1311, 1232, 945, 846, 788, 736cm⁻¹.

¹H-NMR(CDCl₃) δ: 7.50 (1H, d, J=8.4 Hz), 7.56 (1H, dd, J=4.8, 7.5 Hz),7.79 (1H, dd, J=2.2, 8.4 Hz), 7.92 (1H, m), 8.53 (1H, d, J=7.5 Hz),8.70-8.75 (2H, m).

Elemental Analysis for C₁₃H₇N₂OSBr

Calcd. C, 48.92; H, 2.21; N, 8.78.

Found C, 49.05; H, 2.27; N, 8.89.

Example 12

8-Methyl-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of 3-methyl-2-mercaptobenzoic acid (2.40 g, 14.3 mmol),2-cyanopyridine (1.20 g, 11.9 mmol) and pyridine (50.0 ml) was refluxedfor 9 hrs as described in Example 9. After cooling, the precipitatedcrystals were collected by filtration and recrystallized fromhexane-tetrahydrofuran to give the titled compound (1.60 g, 52%)

mp. 197.8-198.5° C.

IR(KBr): 3468, 3063, 1649, 1577, 1537, 1311, 1282, 1232, 1099, 1086,995, 939, 787, 750, 738 cm⁻¹.

¹H-NMR(CDCl₃) δ: 2.59 (3H, s), 7.50-7.57 (3H, m), 7.92 (1H, m), 8.42(1H, m), 8.57 (1H, d, J=7.9 Hz), 8.77 (1H, d, J=4.6 Hz).

Elemental Analysis for C₁₄H₁₀N₂OS

Calcd. C, 66.12; H, 3.96; N, 11.02.

Found C, 66.00; H, 3.94; N, 11.14.

Example 13

6-Methyl-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of 5-methyl-2-mercaptobenzoic acid (1.60 g, 9.5 mmol),2-cyanopyridine (1.10 g, 10.1 mmol) and pyridine (20.0 ml) was refluxedfor 8 hrs as described in Example 9. After cooling, the precipitatedcrystals were collected by filtration and recrystallized fromhexane-ethanol to give the titled compound (1.04 g, 43%).

mp. 219.8-220.8° C.

IR(KBr): 3049, 2916, 1651, 1568, 1537, 1466, 1317, 1280, 1234, 1188,997, 788, 734, 617, 515 cm⁻¹.

¹H-NMR(CDCl₃) δ: 2.50 (3H, s), 7.51-7.59 (3H, m), 7.91 (1H, m) 8.38 (1H,s), 8.54 (1H, d, J=7.9 Hz), 8.73 (1H, d, J=4.4 Hz).

Elemental Analysis for C₁₄H₁₀N₂OS

Calcd. C, 66.12; H, 3.96; N, 11.02.

Found C, 66.02; H, 3.93; N, 11.13.

Example 14

6,7-Dimethoxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of 4,5-dimethoxy-2-mercaptobenzoic acid (2.20 g, 10.2 mmol),2-cyanopyridine (1.10 g, 10.2 mmol) and pyridine (15.0 ml) was refluxedfor 20 hrs as described in Example 9. After cooling, the precipitatedcrystals were collected by filtration and recrystallized fromhexane-chlorobenzene to give the titled compound (1.70 g, 55%).

mp. 236.3-237.5° C.

IR(KBr): 3059, 2970, 1641, 1603, 1531, 1504, 1466, 1398, 1280, 1267,1043, 910, 794, 734, 723 cm⁻¹.

¹H-NMR(CDCl₃) δ: 4.01 (3H, s), 4.03 (3H, s), 6.96 (1H, s), 7.52 (1H, m),7.90 (1H, m), 7.97 (1H, s), 8.54 (1H, d, J=7.9 Hz), 8.71 (1H, d, J=4.5Hz).

Elemental Analysis for C₁₅H₁₂N₂O₃S

Calcd. C, 59.99; H, 4.03; N, 9.33.

Found C, 60.11; H, 4.02; N, 9.35.

Example 15

2-(1H-Pyrrol-2-yl)-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (2.00 g, 11.8 mmol),pyrrole-2-carbonitrile (1.10 g, 11.9 mmol), triethylamine (2.00 ml, 14.3mmol) and toluene (4.0 ml) was refluxed for 15 hrs as described inExample 1. After cooling, the precipitated crystals were collected byfiltration and recrystallized from hexane-ethanol to give the titledcompound (1.90 g, 73%).

mp. 202.4-203.2° C.

IR(KBr): 3269, 1631, 1572, 1543, 1493, 1454, 1396, 1302, 1124, 1101,1049, 887, 742 cm⁻¹.

¹H-NMR(CDCl₃) δ: 6.39 (1H, s), 7.14-7.16 (2H, m), 7.43-7.63 (3H, m),8.49 (1H, dd, J=1.5, 7.7 Hz), 10.10 (1H, br s).

Elemental Analysis for C₁₂H₈N₂OS

Calcd. C, 63.14; H, 3.53; N, 12.27.

Found C, 63.11; H, 3.49; N, 12.35.

Example 16

2-(1,5-Dimethyl-1H-pyrrol-2-yl)-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (2.20 g, 13.3 mmol),1,5-dimethyl-2-pyrrolecarbonitrile (1.40 g, 11.9 mmol), triethylamine(2.50 ml, 17.9 mmol) and toluene (7.0 ml) was refluxed for 24 hrs asdescribed in Example 1. After cooling, the precipitated crystals werecollected by filtration and recrystallized from hexane-ethanol to givethe titled compound (1.30 g, 41%).

mp. 194.3-195.7° C.

IR(KBr): 2951, 2910, 1649, 1574, 1545, 1504, 1460, 1435, 1363, 1290,1234, 1124, 1099, 1068, 864, 740 cm⁻¹.

¹H-NMR(CDCl₃) δ: 2.31 (3H, m), 4.07 (3H, s), 6.07 (1H, d, J=4.1 Hz),7.12 (1H, d, J=4.1 Hz), 7.40 (1H, m), 7.47-7.59 (2H, m), 8.43 (1H, dd,J=1.5, 7.8 Hz).

Elemental Analysis for C₁₄H₁₂N₂OS

Calcd. C, 65.60; H, 4.72; N, 10.93.

Found C, 65.49; H, 4.54; N, 11.04.

Example 17

5-Methyl-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of 6-methyl-2-mercaptobenzoic acid (1.70 g, 10.1 mmol),2-cyanopyridine (1.06 g, 10.2 mmol) and pyridine (30.0 ml) was refluxedat 135° C. for 18 hrs as described in Example 9. The reaction mixturewas concentrated. The residue was subjected to a silica gel columnchromatography and eluted with ethyl acetate. The resultant product wasrecrystallized from ethanol to give the titled compound (0.51 g, 20%).

mp. 150.8-151.3° C.

IR(KBr): 3074, 2970, 1662, 1585, 1574, 1545, 1444, 1439, 1410, 1377,1298, 1273, 1263, 1238, 1184, 1105, 1051, 955, 943, 827, 783, 733 cm⁻¹.

¹H-NMR(CDCl₃) δ: 2.85 (3H, s), 7.38-7.54 (4H, m), 7.89-7.93 (1H, m),8.46-8.49 (1H, m), 8.72-8.74 (1H, m).

Elemental Analysis for C₁₄H₁₀N₂OS

Calcd. C, 66.12; H, 3.96; N, 11.02.

Found C, 60.10; H, 3.98; N, 11.07.

Example 18

8-Methoxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of 3-methoxy-2-mercaptobenzoic acid (1.84 g, 10.0 mmol),2-cyanopyridine (1.05 g, 10.2 mmol) and pyridine (30.0 ml) was refluxedat 135° C. for 18 hrs as described in Example 9. The mixture wasconcentrated. The obtained crystals were recrystallized from ethanol togive the titled compound (0.75 g, 28%).

mp. 191.2-191.4° C.

IR(KBr): 3049, 1657, 1591, 1535, 1467, 1442, 1427, 1332, 1304, 1280,1269, 1234, 1134, 1105, 1060, 1047, 995, 941, 796, 767, 758, 742 cm⁻¹.

¹H-NMR(CDCl₃) δ: 4.01(3H, s), 7.17 (1H, d, J=8.1 Hz), 7.51-7.59 (2H, m),7.87-7.93 (1H, m), 8.16 (1H, d, J=8.0 Hz), 8.55 (1H, d, J=7.9 Hz),8.75-8.76 (1H, m).

Elemental Analysis for C₁₄H₁₀N₂O₂S

Calcd. C, 62.21; H, 3.73; N, 10.36.

Found C, 62.18; H, 3.64; N, 10.49.

Example 19

7-Fluoro-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of 4-fluoro-2-mercaptobenzoic acid (5.00 g, 29.0 mmol),2-cyanopyridine (3.05 g, 29.3 mmol) and pyridine (30.0 ml) was refluxedat 135° C. for 48 hrs as described in Example 9. The reaction mixturewas concentrated. The residue was subjected to a silica gel columnchromatography and eluted with hexane-ethyl acetate (2:1, v/v). Theresultant product was recrystallized from ethanol to give the titledcompound (0.09 g, 1%).

mp. 250.0-250.2° C.

IR(KBr): 3069, 1660, 1606, 1576, 1545, 1477, 1466, 1435, 1396, 1305,1280, 1240, 1120, 1097, 1086, 997, 941, 860, 790, 773, 738 cm⁻¹.

¹H-NMR(CDCl₃) δ: 7.29-7.36 (2H, m), 7.54-7.58 (1H, m), 7.89-7.95 (1H,m), 8.52-8.60 (2H, m), 8.74 (1H, d, J=4.6 Hz)

Elemental Analysis for C₁₃H₇N₂OSF

Calcd. C, 60.46; H, 2.73; N, 10.85.

Found C, 60.34; H, 2.65; N, 11.11.

Example 20

6-Fluoro-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of 5-fluoro-2-mercaptobenzoic acid (1.50 g, 8.7 mmol),2-cyanopyridine (0.92 g, 8.8 mmol) and pyridine (30.0 ml) was refluxedat 135° C. for 48 hrs as described in Example 9. The reaction mixturewas concentrated. The residue was subjected to a silica gel columnchromatography and eluted with hexane-ethyl acetate (2:1, v/v). Theresultant product was recrystallized from ethanol to give the titledcompound (0.09 g, 4%).

mp. 239.9-240.4° C.

IR(KBr): 3061, 1666, 1606, 1577, 1539, 1471, 1439, 1412, 1317, 1302,1267, 1234, 1126, 1099, 1055, 995, 950, 918, 900, 885, 819, 792, 734,707 cm⁻¹.

¹H-NMR(CDCl₃) δ: 7.42-7.48 (1H, m), 7.48-7.58 (1H, m), 7.62-7.66 (1H,m), 7.90-7.85 (1H, m), 8.23-8.27 (1H, m), 8.55 (1H, d, J=7.9 Hz),8.74-8.75 (1H, m).

Elemental Analysis for C₁₃H₇N₂OSF

Calcd. C, 60.46; H, 2.73; N, 10.85.

Found C, 60.48; H, 2.77; N, 10.99.

Example 21

5-Fluoro-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of 6-fluoro-2-mercaptobenzoic acid (5.00 g, 29.0 mmol),2-cyanopyridine (3.05 g, 29.3 mmol) and pyridine (30.0 ml) was refluxedat 135° C. for 48 hrs as described in Example 9. The reaction mixturewas concentrated. The residue was subjected to a silica gel columnchromatography and eluted with hexane-ethyl acetate (2:1, v/v). Theresultant product was recrystallized from ethanol to give the titledcompound (0.11 g, 1%).

mp. 256.5-257.2° C.

IR(KBr): 3065, 1668, 1601, 1576, 1539, 1462, 1448, 1433, 1298, 1273,1251, 1238, 1086, 1057, 997, 945, 914, 800, 781, 738 cm⁻¹.

¹H-NMR(CDCl₃) δ: 7.24-7.30 (1H, m), 7.41 (1H, d, J=7.9 Hz), 7.53-7.66(2H, m), 7.89-7.95 (1H, m), 8.50 (1H, d, J=7.9 Hz), 8.73-8.74 (1H, m).

Elemental Analysis for C₁₃H₇N₂OSF

Calcd. C, 60.46; H, 2.73; N, 10.85.

Found C, 60.11; H, 2.68; N, 11.04.

Example 22

2-(2-Pyridyl)-4H-pyrido[3,2-e][1,3]thiazine-4-one

A mixture of 2-mercaptonicotinic acid (5.00 g, 32.2 mmol),2-cyanopyridine (3.39 g, 32.5 mmol) and pyridine (30.0 ml) was refluxedat 135° C. for 72 hrs as described in Example 9. The mixture wasconcentrated. The residue was subjected to a silica gel columnchromatography and eluted with hexane-ethyl acetate (1:1, v/v). Theresultant product was recrystallized from ethanol to give the titledcompound (0.10 g, 1%)

mp. 234.7-234.9° C.

IR(KBr): 3069, 1666, 1568, 1543, 1467, 1439, 1402, 1307, 1290, 1236,1217, 1114, 1074, 1041, 997, 943, 788, 761 cm⁻¹.

¹H-NMR(CDCl₃) δ: 7.55-7.60 (2H, m), 7.90-7.96 (1H, m), 8.54 (1H, d,J=7.9 Hz), 8.75-8.78 (2H, m), 8.85-8.87 (1H, m).

Elemental Analysis for C₁₂H₇N₃OS

Calcd. C, 59.71; H, 2.29; N, 17.42.

Found C, 59.75; H, 2.71; N, 17.58.

Example 23

Methyl [6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]acetate

A mixture of methyl thiosalicylate (0.84 g, 5.0 mmol),2-acetoxy-6-cyanopyridine (0.90 g, 5.0 mmol), triethylamine (1.10 ml,7.5 mmol) and toluene (30 ml) was refluxed for 48 hrs as described inExample 1. The reaction mixture was concentrated. The precipitatedcrystals were collected by filtration and recrystallized from ethanol togive the titled compound (0.67 g, 43%).

mp. 180.1-180.3° C.

IR(KBr): 1741, 1653, 1570, 1527, 1439, 1371, 1296, 1277, 1224, 1055,812, 736 cm⁻¹.

¹H-NMR(CDCl₃) δ: 2.20 (3H, s), 5.35 (2H, s), 7.58-7.72 (4H, m) 7.92 (1H,t, J=7.8 Hz), 8.47 (1H, d, J=7.8 Hz), 8.48-8.57 (1H, m).

Elemental Analysis for C₁₆H₁₂N₂O₃S

Calcd. C, 61.53; H, 3.87; N, 8.97.

Found C, 61.59; H, 3.73; N, 9.06.

Reference Example 2

2-Mercapto-3,5-dimethylbenzoic acid

A mixture of 2-amino-3,5-dimethylbenzoic acid (5.6 g, 33.9 mmol), sodiumhydroxide (1.5 g, 37.5 mmol), sodium nitrite (2.3 g, 34.0 mmol) andwater (40 ml) was added dropwise to a mixture of concentratedhydrochloric acid (10 ml) and ice (10 g) under cooling with ice whileadding ice in order to keep the reaction temperature under 5° C. Thereaction mixture was stirred under ice-cooling condition for 30 minutes,neutralized with potassium acetate and added to a solution of potassiumo-ethyl dithiocarbonate (16.9 g, 105.4 mmol) in water (50 ml) at 80° C.After stirring at the same temperature for 20 minutes, the reactionmixture was acidified (pH 3) by use of concentrated hydrochloric acid.The water layer was separated. 10% aqueous sodium hydroxide solution (30ml) was added to the oily substance and the mixture was stirred at 80°C. for 2 hrs. Furthermore, sodium hydrogen sulfite (4.0 g) was added tothe mixture, and the mixture was stirred at the same temperature for 10minutes. The reaction mixture was filtered and the filtrate wasacidified (about pH 4) by use of concentrated hydrochloric acid. Theprecipitate was collected by filtration and dissolved in a mixture ofmethanol (5 ml) and diisopropylether (80 ml), dried and concentratedunder reduced pressure to give the titled compound as crystals (3.6 g,58%).

¹H-NMR (CDCl₃) δ: 2.31 (3H, s), 2.36 (3H, s), 6.20 (1H, b s), 7.19 (1H,s), 7.86 (1H, s).

Example 24

6,8-Dimethyl-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of 2-mercapto-3,5-dimethylbenzoic acid (1.6 g, 8.8 mmol),2-cyanopyridine (1.0 g, 9.7 mmol) and pyridine (15 ml) was refluxed for12 hrs as described in Example 9. After cooling, the precipitatedcrystals were collected by filtration and recrystallized fromhexane-chlorobenzene to give the titled compound (1.2 g, 52%).

mp. 245.0-245.8° C.

IR(KBr): 3047, 2990, 1645, 1572, 1537, 1462, 1329, 1234, 1180, 995, 792,740 cm⁻¹.

¹H-NMR(CDCl₃) δ: 2.46 (3H, s), 2.55 (3H, s), 7.38 (1H, s), 7.53 (1H, m),7.91 (1H, m), 8.26 (1H, s), 8.57 (1H, d), 8.76 (1H, d).

Elemental Analysis for C₁₅H₁₂N₂OS

Calcd. C, 67.14; H, 4.51; N, 10.44.

Found C, 67.20; H, 4.49; N, 10.52.

Example 25

2-(4-Methoxy-2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (2.0 g, 11.7 mmol),4-methoxy-2-cyanopyridine (1.5 g, 11.1 mmol), triethylamine (2.5 ml,17.9 mmol) and toluene (5 ml) was refluxed for 12 hrs as described inExample 1. The precipitated crystals were collected by filtration andrecrystallized from hexane-chlorobenzene to give the titled compound(2.4 g, 81%).

mp. 214.1-214.6° C.

IR(KBr): 3080, 1655, 1591, 1570, 1533, 1475, 1305, 1028, 821 cm⁻¹.

¹H-NMR(CDCl₃) δ: 3.97 (3H, s), 7.03 (1H, m), 7.59-7.69 (3H, m); 8.07(1H, d, J=2.5 Hz), 8.50-8.56 (2H, m).

Elemental Analysis for C₁₄H₁₀N₂O₂S

Calcd. C, 62.21; H, 3.73; N, 10.36.

Found C, 62.37; H, 3.70; N, 10.42.

Example 26

Ethyl

6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridinecarboxylate

A mixture of methyl thiosalicylate (2.0 g, 11.9 mmol), ethyl6-cyano-2-pyridinecarboxylate (2.1 g, 11.9 mmol), triethylamine (3.0 ml,21.5 mmol) and toluene (6 ml) was refluxed for 12 hrs as described inExample 1. The precipitated crystals were collected by filtration andrecrystallized from diisopropylether-tetrahydrofuran to give the titledcompound (3.0 g, 80%).

mp. 170.0-172.2° C.

IR(KBr): 3069, 2986, 1738, 1709, 1676, 1574, 1541, 1440, 1232, 912, 746,729 cm⁻¹.

¹H-NMR(CDCl₃) δ: 1.50 (3H, t), 4.54 (2H, q), 7.63-7.73 (3H, m), 8.07(1H, m), 8.32 (1H, d), 8.56 (1H, d), 8.71 (1H, d)

Elemental Analysis for C₁₆H₁₂N₂O₃S

Calcd. C, 61.53; H, 3.87; N, 8.97.

Found C, 61.52; H, 3.95; N, 9.14.

Example 27

Ethyl 2-(4-oxo-4H-1,3-benzothiazin-2-yl)isonicotinate

A mixture of methyl thiosalicylate (3.0 g, 17.8 mmol), ethyl2-cyanoisonicotinate (3.1 g, 17.8 mmol), triethylamine (5.0 ml, 35.8mmol) and toluene (10 ml) was refluxed for 8 hrs as described inExample 1. The precipitated crystals were collected by filtration andrecrystallized from diisopropylether-chlorobenzene to give the titledcompound (4.0 g, 71%).

mp. 235.9-236.7° C.

IR(KBr): 2993, 1720, 1670, 1541, 1307, 1292, 1219, 1016, 869, 763, 734cm⁻¹.

¹H-NMR(CDCl₃) δ: 1.45 (3H, t), 4.48 (2H, q), 7.61-7.74 (3H, m), 8.12(1H, m), 8.87 (1H, m), 8.88 (1H, d), 9.04 (1H, s).

Elemental Analysis for C₁₆H₁₂N₂O₃S

Calcd. C, 61.53; H, 3.87; N, 8.97.

Found C, 61.47; H, 3.73; N, 8.99.

Example 28

Methyl 6-(4-oxo-4H-1,3-benzothiazin-2-yl)nicotinate

A mixture of methyl thiosalicylate (2.1 g, 12.3 mmol), methyl6-cyanonicotinate (2.0 g, 12.3 mmol), triethylamine (3.0 ml, 21.5 mmol)and toluene (6 ml) was refluxed for 12 hrs as described in Example 1.The precipitated crystals were collected by filtration andrecrystallized from diisopropylether-chlorobenzene to give the titledcompound (2.1 g, 58%).

mp. 233.3-333.6° C.

IR(KBr): 2951, 1728, 1660, 1572, 1537, 1439, 1294, 1277, 1114, 1095,783, 727 cm⁻¹.

¹H-NMR(CDCl₃) δ: 4.01 (3H, s), 7.62-7.74 (3H, m), 8.48-8.63 (3H, m),9.30 (1H, m).

Elemental Analysis for C₁₅H₁₀N₂O₃S

Calcd. C, 60.39; H, 3.38; N, 9.39.

Found C, 60.43; H, 3.55; N, 9.39.

Example 29

7-Chloro-2-(4-methyl-2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of 4-chloro-2-mercaptobenzoic acid (3.0 g, 15.9 mmol),2-cyano-4-methylpyridine (1.9 g, 16.0 mmol) and pyridine (15 ml) wasrefluxed for 9 hrs as described in Example 9. After cooling, theprecipitated crystals were collected by filtration, subjected to asilica gel column chromatography, eluted with ethyl acetate-methanol(5:1, v/v) and recrystallized from chlorobenzene-hexane to give thetitled compound (1.47 g, 32%)

mp. 246.2-246.7° C.

IR(KBr): 2959, 1664, 1585, 1566, 1535, 1379, 1292, 1275, 1093, 860, 815,771 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.48 (3H, s), 7.36 (1H, d, J=4.8 Hz), 7.55-7.59 (2H,m), 8.38 (1H, s), 8.47 (1H, d, J=8.3 Hz), 8.58 (1H, d, J=4.8 Hz).

Elemental Analysis for C₁₄H₉N₂OSCl

Calcd. C, 58.23; H, 3.14; N, 9.70.

Found C, 58.29; H, 3.16; N, 9.73.

Example 30

7-Chloro-2-(2-pyrazyl)-4H-1,3-benzothiazine-4-one

A mixture of 4-chloro-2-mercaptobenzoic acid (3.0 g, 15.9 mmol),2-cyanopyrazine (1.8 g, 16.7 mmol) and pyridine (25 ml) was refluxed for6 hrs as described in Example 9. After cooling, the precipitatedcrystals were collected by filtration, subjected to a silica gel columnchromatography, eluted with ethyl acetate-methanol (5:1, v/v) andrecrystallized from diisopropylether-chlorobenzene to give the titledcompound (1.71 g, 39%).

mp. 240.6-240.9° C.

IR(KBr): 3074, 1666, 1649, 1589, 1562, 1535, 1466, 1404, 1381, 1296,1280, 1097, 1016, 939, 771 cm⁻¹.

¹H-NMR (CDCl₃) δ: 7.59-7.62 (2H, m), 8.50 (1H, d, J=9.0 Hz), 8.72 (1H,s), 8.86 (1H, d, J=2.4 Hz), 9.70 (1H, d, J=1.2 Hz).

Elemental Analysis for C₁₂H₆N₃OSCl

Calcd. C, 52.27; H, 2.19; N, 15.24.

Found C, 52.26; H, 2.23; N, 15.30.

Example 31

2-[6-(Propylamino)-3-pyridyl]-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (2.5 g, 15 mmol),6-(propylamino)nicotinenitrile (1.6 g, 12.3 mmol), triethylamine (3.0ml, 21.5 mmol) and toluene (6 ml) was refluxed for 8 hrs as described inExample 1. After cooling, the precipitated crystals were collected byfiltration and recrystallized from diisopropylether-chlorobenzene togive the titled compound (0.70 g, 23%) as crystals.

mp. 210.1-210.6° C.

IR (KBr): 3285, 3153, 2955, 2870, 1631, 1610, 1496, 1406, 1356, 1296,1265, 1122, 1105, 1033, 918, 841, 738 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.02 (3H, t, J=7.4 Hz), 1.70 (2H, m), 3.35 (2H, m),5.29 (1H, br s), 6.46 (1H, d, J=9.0 Hz), 7.48-7.64 (3H, m), 8.29 (1H,dd, J=2.4, 9.0 Hz), 8.50 (1H, dd, J=1.6, 7.7 Hz), 8.94 (1H, d, J=2.4 Hz)

Elemental Analysis for C₁₆H₁₅N₃OS

Calcd. C, 64.62; H, 5.08; N, 14.13.

Found C, 64.55; H, 4.96; N, 14.07.

Example 32

2-[6-(Benzylamino)-3-pyridyl]-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (1.6 g, 9.8 mmol),6-benzylaminonicotinenitrile (1.3 g, 6.4 mmol), triethylamine (2.0 ml,14.3 mmol) and toluene (8 ml) was refluxed for 30 hrs as described inExample 1. After cooling, the precipitated crystals were collected byfiltration and recrystallized from diisopropylether-tetrahydrofuran togive the titled compound (0.80 g, 36%) as crystals.

mp. 194.3-196.2° C.

IR (KBr): 3269, 3080, 1633, 1603, 1493, 1452, 1400, 1311, 1248, 1165,1128, 1101, 920, 821, 740 cm⁻¹.

¹H-NMR (CDCl₃) δ: 4.63 (2H, d, J=5.8 Hz), 5.60 (1H, br s), 6.48 (1H, d,J=8.9 Hz), 7.35 (5H, m), 7.48-7.63 (3H, m), 8.28 (1H, dd, J=2.4, 8.9Hz), 8.50 (1H, dd, J=1.7, 7.5 Hz), 8.96 (1H, d, J=2.4 Hz).

Elemental Analysis for C₂₀H₁₅N₃OS

Calcd. C, 69.54; H, 4.38; N, 12.17.

Found C, 69.44; H, 4.27; N, 12.20.

Example 33

2-[6-(1-Pyrrolidinyl)-3-pyridyl]-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (1.6 g, 9.8 mmol),6-(1-pyrrolidinyl)nicotinenitrile (1.4 g, 8.1 mmol), triethylamine (2.0ml, 14.3 mmol) and toluene (10 ml) was refluxed for 20 hrs as describedin Example 1. After cooling, the precipitated crystals were collected byfiltration and recrystallized from diisopropylether-chlorobenzene togive the titled compound (1.09 g, 43%) as crystals.

mp. 221.0-223.1° C.

IR (KBr): 2966, 2872, 1637, 1595, 1506, 1458, 1313, 1259, 1236, 1170,1126, 1103, 916, 800, 760 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.06 (4H, m), 3.57 (4H, m), 6.42 (1H, d, J=9.1 Hz),7.47-7.64 (3H, m), 8.31 (1H, dd, J=2.4, 9.1 Hz), 8.50 (1H, dd, J=1.2,7.7 Hz), 8.98 (1H, d, J=2.4 Hz).

Elemental Analysis for C₁₇H₁₅N₃OS

Calcd. C, 66.00; H, 4.89; N, 13.58.

Found C, 65.98; H, 4.85; N, 13.57.

Example 34

2-[6-(1-Piperidino)-3-pyridyl]-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (1.9 g, 11.4 mmol),6-(1-piperidino)nicotinenitrile (1.4 g, 7.5 mmol), triethylamine (2.0ml, 14.3 mmol) and toluene (10 ml) was refluxed for 24 hrs as describedin Example 1. After cooling, the precipitated crystals were collected byfiltration and recrystallized from diisopropylether-chlorobenzene togive the titled compound (0.41 g, 16%) as crystals.

mp. 191.2-191.7° C.

IR (KBr): 2922, 2854, 1651, 1601, 1504, 1439, 1238, 1124, 1099, 740cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.66-1.69 (6H, m), 3.73 (4H, m), 6.67 (1H, d, J=9.3Hz), 7.47-7.62 (3H, m), 8.30 (1H, dd, J=2.5, 9.3 Hz), 8.50 (1H, dd,J=1.6, 7.7 Hz), 8.96 (1H, d, J=2.5 Hz).

Elemental Analysis for C₁₈H₁₇N₃OS

Calcd. C, 66.85; H, 5.30; N, 12.99.

Found C, 66.87; H, 5.29; N, 12.98.

Example 35

2-[6-(4-Morpholino)-3-pyridyl]-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (1.7 g, 10.4 mmol),6-(4-morpholino)nicotinenitrile (1.3 g, 6.8 mmol), triethylamine (2.0ml, 14.3 mmol) and toluene (5 ml) was refluxed for 20 hrs as describedin Example 1. After cooling, the precipitated crystals were collected byfiltration and recrystallized from hexane-chlorobenzene to give thetitled compound (0.48 g, 21%) as crystals.

mp. 232.6-234.4° C.

IR (KBr): 2912, 1664, 1604, 1504, 1433, 1236, 1116, 1049, 947, 808, 744cm⁻¹.

¹H-NMR (CDCl₃) δ: 3.72 (4H, t, J=4.5 Hz), 3.82 (4H, t, J=4.5 Hz), 6.68(1H, d, J=9.1 Hz), 7.49-7.64 (3H, m), 8.35 (1H, dd, J=2.5, 9.1 Hz), 8.51(1H, dd, J=1.6, 7.7 Hz), 8.99 (1H, d, J=2.5 Hz).

Elemental Analysis for C₁₇H₁₅N₃O₂S

Calcd. C, 62.75; H, 4.65; N, 12.91.

Found C, 62.72; H, 4.59; N, 12.94.

Example 36

2-{6-[(4-Chlorophenyl)thio]-3-pyridyl}-4H-1,3-benzothiazine -4-one

A mixture of methyl thiosalicylate (1.6 g, 9.6 mmol),6-[(4-chlorophenyl)thio]nicotinenitrile (2.0 g, 8.1 mmol), triethylamine(2.0 ml, 14.3 mmol) and toluene (5 ml) was refluxed for 20 hrs asdescribed in Example 1. After cooling, the precipitated crystals werecollected by filtration and recrystallized from hexane-chlorobenzene togive the titled compound (1.6 g, 52%) as crystals.

mp. 221.5-222.0° C.

IR (KBr): 3057, 1658, 1572, 1545, 1512, 1477, 1442, 1296, 1242, 1091,1012, 922, 819, 734 cm⁻¹.

¹H-NMR (CDCl₃) δ: 7.03 (1H, d, J=8.6 Hz), 7.46 (2H, d, J=8.4 Hz), 7.53(1H, m), 7.57 (2H, d, J=8.4 Hz), 7.61-7.72 (2H, m), 8.29 (1H, dd, J=2.2,8.6 Hz), 8.52 (1H, dd, J=1.8, 7.5 Hz), 9.13 (1H, d, J=2.2 Hz).

Elemental Analysis for C₁₉H₁₁N₂OS₂Cl

Calcd. C, 59.60; H, 2.90; N, 7.32.

Found C, 59.50; H, 2.79; N, 7.14.

Example 37

6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-N-propylnicotinamide

A mixture of methyl thiosalicylate (2.2 g, 13.3 mmol),6-cyano-N-propylnicotinamide (1.2 g, 6.5 mmol), triethylamine (2.0 ml,14.3 mmol) and toluene (4 ml) was refluxed for 5 hrs as described inExample 1. After cooling, the precipitated crystals were collected byfiltration and recrystallized from diisopropylether-chloroform to givethe titled compound (1.4 g, 67%) as crystals.

mp. 268.0-268.6° C.

IR (KBr): 3354, 3059, 2962, 2937, 1660, 1631, 1537, 1514, 1323, 1273,742 cm⁻¹.

¹H-NMR (DMSO-d₆) δ: 0.93 (3H, t, J=7.3 Hz), 1.58 (2H, m), 3.27 (2H, m),7.74 (1H, m), 7.82 (1H, m), 7.94 (1H, d, J=7.9 Hz), 8.36 (1H, d, J=7.9Hz), 8.42-8.48 (2H, m), 8.87 (1H, m), 9.15 (1H, s).

Elemental Analysis for C₁₇H₁₅N₃O₂S

Calcd. C, 62.75; H, 4.65; N, 12.91.

Found C, 62.72; H, 4.59; N, 12.95.

Example 38

6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridinecarboxamide

A mixture of methyl thiosalicylate (1.1 g, 6.4 mmol),6-cyano-2-pyridinecarboxamide (0.47 g, 3.1 mmol), triethylamine (1.0 ml,7.1 mmol) and toluene (3 ml) was refluxed for 6 hrs as described inExample. After cooling, the precipitated crystals were collected byfiltration and recrystallized from hexane-ethanol to give the titledcompound (0.63 g, 70%).

mp. 294.6-294.9° C.

IR (KBr): 3447, 3123, 1726, 1662, 1574, 1545, 1388, 1300, 1095, 976,742, 507 cm⁻¹.

¹H-NMR (DMSO-d₆) δ: 7.75 (1H, m), 7.85-7.89 (2H, m), 8.00-8.03 (2H, m),8.28-8.39 (3H, m), 8.51 (1H, dd, J=1.8, 7.1 Hz).

Elemental Analysis for C₁₄H₉N₃O₂S

Calcd. C, 59.35; H, 3.20; N, 14.83.

Found C, 59.39; H, 3.06; N, 14.96.

Reference Example 3

2-Mercapto-4-methylbenzoic acid

(1) Methyl 4-methylsalicylate (10.7 g, 64 mmol) was dissolved in DMF(100 ml). N,N-Dimethylthiocarbamoyl chloride (8.0 g, 65 mmol) and1,4-diazabicyclo[2,2,2]octane (7.2 g, 65 mmol) were added thereto withthe mixture stirring. The reaction mixture was stirred at roomtemperature for 20 hrs, poured into water and extracted with ethylacetate. The extract was washed with water and dried, and the solventwas evaporated under reduced pressure. The residue was subjected to asilica gel column chromatography, eluted with hexane-ethyl acetate (3:1,v/v), recrystallized from ethyl acetate-hexane to give methyl

2-(N,N-dimethylaminothiocarbamoyl)oxy-4-methylbenzoate (9.1 g, 55%) ascrystals (mp. 99.9-100.2° C.).

IR (KBr): 2947, 1724, 1620, 1537, 1435, 1394, 1288, 1257, 1236, 1174,1128, 1086 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.41 (3H, s), 3.39 (3H, s), 3.46 (3H, s), 3.82 (3H,s), 6.93 (1H, s), 7.11 (1H, d, J=8.0 Hz), 7.90 (1H, d, J=8.0 Hz).

Elemental Analysis for C₁₂H₁₅NO₃S

Calcd. C, 56.90; H, 5.97; N, 5.53.

Found C, 56.91; H, 5.97; N, 5.44.

(2) Methyl 2-(N,N-dimethylaminothiocarbamoyl)oxy-4-methylbenzoate (6.7g, 26 mmol) was melted at 190° C. for 16 hrs. After cooling the reactionmixture was subjected to a silica gel column chromatography, eluted withhexane-ethyl acetate (3:2, v/v) and recrystallized from ethylacetate-hexane to give methyl2-(N,N-dimethylaminocarbamoyl)thio-4-methylbenzoate (5.1 g, 75%) ascrystals (mp. 79.4-80.0° C.)

IR (KBr): 2949, 1728, 1666, 1601, 1433, 1361, 1292, 1257, 1120, 1097,1055, 908 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.38 (3H, s), 3.07 (6H, br s), 3.86 (3H, S), 7.22 (1H,d, J=7.9 Hz), 7.43 (1H, s), 7.81 (1H, d, J=7.9 Hz).

Elemental Analysis for C₁₂H₁₅NO₃S

Calcd. C, 56.90; H, 5.97; N, 5.53.

Found C, 56.74; H, 5.88; N, 5.26.

(3) A mixture of methyl2-(N,N-dimethylaminocarbamoyl)thio-4-methylbenzoate (2.0 g, 7.9 mmol)and 10% aqueous sodium hydroxide solution (15 g, 38 mmol) was stirred at100° C. for 14 hrs. After cooling, the reaction mixture was acidified(pH 4) by use of 1 N hydrochloric acid. The precipitated crystals werecollected by filtration, dissolved in ethyl acetate and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure to give 3-mercapto-4-methylbenzoic acid (1.3 g, ca. 100%) ascrystals.

¹H-NMR (CDCl₃+DMSO-d₆) δ: 2.32 (3H, s), 5.19 (1H, br s), 6.95 (1H, d,J=8.0 Hz), 7.11 (1H, s), 7.94 (1H, d, J=8.0 Hz).

Example 39

7-Methyl-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of 2-mercapto-4-methylbenzoic acid (2.0 g, 12 mmol),2-cyanopyridine (1.4 g, 13 mmol) and pyridine (8 ml) was refluxed for 14hrs as described in Example 9. After cooling, the precipitated crystalswere collected by filtration, subjected to a silica gel columnchromatography, eluted with ethyl acetate-methanol (5:1, v/v) andrecrystallized from hexane-tetrahydrofuran to give the titled compound(1.4 g, 48%).

mp. 225.0-225.2° C.

IR (KBr): 3076, 3001, 1658, 1606, 1568, 1539, 1464, 1305, 1282, 790cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.49 (3H, s), 7.39 (1H, s), 7.43 (1H, d, J=8.1 Hz),7.54 (1H, m), 7.91 (1H, m), 8.43 (1H, d, J=8.1 Hz), 8.54 (1H, d, J=7.9Hz), 8.74 (1H, m).

Elemental Analysis for C₁₄H₁₀N₂OS

Calcd. C, 66.12; H, 3.96; N, 11.02.

Found C, 66.28; H, 3.93; N, 11.03.

Example 40

2-[6-(Hydroxymethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one

A mixture of [6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methylacetate (0.30 g, 1.00 mmol), potassium carbonate (0.004 g, 0.03 mmol)and methanol (30 ml) was stirred under nitrogen atmosphere at roomtemperature for 2 hrs. The reaction mixture was concentrated, dissolvedin hot ethanol (10 ml) and filtered. The filtrate was concentrated underreduced pressure and the residue was recrystallized from ethanol to givethe titled compound (0.19 g, 70%).

mp. 208.2-208.7° C.

IR (KBr): 3385, 1628, 1589, 1570, 1525, 1444, 1302, 1089, 1062, 746cm⁻¹.

¹H-NMR (CDCl₃) δ: 3.40 (1H, t, J=5.2 Hz), 4.91 (2H, d, J=5.2 Hz), 7.53(2H, d, J=7.8 Hz), 7.61-7.73 (3H, m), 7.92 (1H, t, J=7.8 Hz), 8.46 (1H,d, J=7.7 Hz), 8.54-8.57 (1H, m).

Elemental Analysis for C₁₄H₁₀N₂O₂S

Calcd. C, 62.21; H, 3.73; N, 10.36.

Found C, 62.00; H, 3.56; N, 10.25.

Example 41

2-(6-Phenoxy-2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (0.34 g, 2.0 mmol),2-cyano-6-phenoxypyridine (0.40 g, 2.0 mmol), triethylamine (0.45 ml,3.1 mmol) and toluene (30 ml) was refluxed for 48 hrs as described inExample 1. After cooling, the precipitated crystals were collected byfiltration and recrystallized from ethanol to give the titled compound(0.18 g, 26%) as crystals.

mp. 160.8-161.3° C.

IR(KBr): 1656, 1572, 1531, 1487, 1439, 1263, 1240, 912, 744 cm⁻¹.

¹H-NMR(CDCl₃) δ: 7.12 (1H, d, J=8.3 Hz), 7.25-7.29 (3H, m), 7.45-7.52(3H, m), 7.61-7.64 (2H, m), 7.88-7.90 (1H, m), 8.25 (1H, d, J=7.4 Hz),8.51-8.54 (1H, m).

Elemental Analysis for C₁₉H₁₂N₂O₂S

Calcd. C, 68.66; H, 3.64; N, 8.34.

Found C, 68.26; H, 3.53; N, 8.37.

Example 42

2-[6-(1-Piperidyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (0.36 g, 2.1 mmol),2-cyano-6-(1-piperidinyl)pyridine (0.40 g, 2.1 mmol), triethylamine(0.45 ml, 3.1 mmol) and toluene (50 ml) was refluxed for 48 hrs asdescribed in Example 1. The solvent was concentrated under reducedpressure. The residue was subjected to a silica gel columnchromatography and eluted with hexane-ethyl acetate (2:1, v/v). Theobtained crystals were recrystallized from hexane-ethyl acetate to givethe titled compound (0.08 g, 13%) as crystals.

mp. 178.7° C. (decomposed).

IR(KBr): 1658, 1595, 1570, 1529, 1485, 1440, 1290, 1253, 1242, 1124,1095, 1064, 976, 792 cm⁻¹.

¹H-NMR(CDCl₃) δ: 1.70 (6H, s), 3.65 (4H, s), 6.86 (1H, d, J=8.5 Hz),7.55-7.67 (4H, m), 7.78 (1H, d, J=7.3 Hz), 8.53 (1H, d, J=7.2 Hz).

Elemental Analysis for C₁₈H₁₇N₃OS·0.1H₂O

Calcd. C, 66.48; H, 5.26; N, 12.92.

Found C, 66.41; H, 5.09; N, 12.67.

Reference Example 4

2-Cyano-6-methylthiopyridine

(1) 15% sodium thiomethoxide (119 ml, 254 mmol) was added to a solutionof 2,6-dichloropyridine (25.0 g, 169 mmol) and tetrabutylammoniumchloride (1.64 g, 5.1 mmol) in toluene (75 ml), and the mixture wasstirred at 110° C. for 3 hrs. The reaction mixture was extracted withtoluene, washed with saturated brine, dried and concentrated underreduced pressure. Acetic acid (120 ml) was added to the residue. 30%hydrogen peroxide solution (45 ml, 398 mmol was added dropwise to themixture, and the mixture was stirred at 60° C. for 30 minutes and 90° C.for 18 hrs. After cooling, the reaction mixture was poured intoice-water and extracted with ethyl acetate. The extract was successivelywashed with saturated brine, 15% aqueous sodium hydroxide solution andsaturated brine and dried, and the solvent was evaporated under reducedpressure to give 2-chloro-6-methylsulfonylpyridine (26.3 g, 81%) ascrystals.

¹H-NMR (CDCl₃) δ: 3.26 (3H, s), 7.26-7.28 (1H, m), 7.93 (1H, t, J=7.8Hz), 8.00-8.03 (1H, m).

(2) A mixture of 2-chloro-6-methylsulfonylpyridine (13.0 g, 67.8 mmol),sodium cyanide (6.69 g, 136 mmol) and DMF (150 ml) was stirred at 170°C. for 18 hrs. After cooling, the reaction mixture was poured into waterand extracted with ethyl acetate. The extract was washed with saturatedbrine and dried, and the solvent was evaporated under reduced pressure.The residue was subjected to a silica gel column chromatography andeluted with hexane-ethyl acetate (2:1, v/v) to give2-chloro-6-cyanopyridine (6.67 g, 71%) as crystals (mp. 82.9-83.1° C.).

IR (KBr): 2253, 1572, 1431, 1161, 1143, 912, 854, 744 cm⁻¹.

¹H-NMR (CDCl₃) δ: 7.57 (1H, d, J=8.0 Hz), 7.65 (1H, d, J=8.1 Hz), 7.82(1H, t, J=7.8 Hz).

(3) A mixture of 2-chloro-6-cyanopyridine (0.70 g, 5.0 mmol), sodiumthiomethoxide (0.39 g, 5.5 mmol) and tetrahydrofuran (50 ml) was stirredat 90° C. for 18 hrs. The reaction mixture was concentrated underreduced pressure, combined with water and extracted with ethyl acetate.The extract was washed with saturated brine and dried, and the solventwas evaporated under reduced pressure to give the titled compound as anoil (0.76 g, 98%).

IR (Neat): 2253, 2237, 1730, 1697, 1576, 1550, 1427, 1161, 1145, 912,742 cm⁻¹.

¹H-NMR(CDCl₃) δ: 2.57 (3H, s), 7.36 (2H, d, J=7.8 Hz), 7.56-7.60 (1H,m).

Example 43

2-(6-Methylthio-2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (0.93 g, 5.5 mmol),2-cyano-6-methylthiopyridine (0.83 g, 5.5 mmol), triethylamine (1.17 ml,8.3 mmol) and toluene (30 ml) was refluxed for 48 hrs as described inExample 1. The solvent was concentrated under reduced pressure. Theresidue was recrystallized from ethanol to give the titled compound(0.57 g, 37%) as crystals.

mp. 207.2-207.8° C.

IR(Neat): 1651, 1572, 1525, 1427, 1232, 1149, 1093, 983, 723 cm⁻¹.

¹H-NMR(CDCl₃) δ: 2.72 (3H, s), 7.41 (1H, d, J=8.0 Hz), 7.42-7.71 (4H,m), 8.19-8.22 (1H, m), 8.54-8.57 (1H, m).

Elemental Analysis for C₁₄H₁₀N₂OS₂

Calcd. C, 58.72; H, 3.52; N, 9.78.

Found C, 58.76; H, 3.69; N, 9.73.

Example 44

2-(6-Methylsulfinyl-2-pyridyl)-4H-1,3-benzothiazine-4-one

2-(6-Methylthio-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.28 g, 1.0 mmol)obtained in Example 43 was dissolved in chloroform (30 ml). To thestirred mixture was added dropwise a solution of 3-chloroperbenzoic acid(ca. 70%, 0.25 g, 1.0 mmol) in chloroform (10 ml). The reaction mixturewas stirred for 1 hr and concentrated under reduced pressure. Theresidue was subjected to a silica gel column chromatography and elutedwith 10% methanol-chloroform and recrystallized from ethanol to give thetitled compound (0.19 g, 64%) as crystals.

mp. 256.5° C. (decomposed).

IR(Neat): 1660, 1568, 1531, 1435, 1298, 1244, 1053, 993, 817, 734 cm⁻¹.

¹H-NMR(CDCl₃) δ: 2.99 (3H, s), 7.60-7.74 (3H, m), 8.15-8.27 (1H, m),8.28 (1H, d, J=7.7 Hz), 8.55-8.62 (2H, m)

Elemental Analysis for C₁₄H₁₀N₂O₂S₂

Calcd. C, 55.61; H, 3.33; N, 9.26.

Found C, 55.47; H, 3.59; N, 9.13.

Example 45

2-(6-Methylsulfonyl-2-pyridyl)-4H-1,3-benzothiazine-4-one

2-(6-Methylthio-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.28 g, 1.0 mmol)obtained in Example 43 was dissolved in chloroform (30 ml). To thestirred mixture was added dropwise a solution of 3-chloroperbenzoic acid(ca. 70%, 0.38 g, 2.2 mmol) in chloroform (10 ml). The reaction mixturewas stirred for 3 hr and concentrated under reduced pressure. Theresidue was subjected to a silica gel column chromatography and elutedwith 10% methanol-chloroform and recrystallized from ethanol to give thetitled compound (0.19 g, 61%) as crystals.

mp. 238.2-239.5° C. (decomposed).

IR(Neat): 1652, 1572, 1537, 1305, 1170, 1124, 1095, 1062, 950, 775 cm⁻¹.

¹H-NMR(CDCl₃) δ: 3.39 (3H, s), 7.63-7.74 (3H, m), 8.23 (1H, d, J=7.8Hz), 8.31 (1H, d, J=7.8 Hz), 8.57 (1H, d, J=7.6 Hz), 8.77 (1H, d, J=7.7Hz).

Elemental Analysis for C₁₄H₁₀N₂O₃S₂

Calcd. C, 52.08; H, 3.25; N, 8.67.

Found C, 51.83; H, 3.02; N, 8.50.

Example 46

2-{6-[(4-methylphenyl)thio]-2-pyridyl}-4H-1,3-benzothiazine -4-one

A mixture of methyl thiosalicylate (0.37 g, 2.2 mmol),2-cyano-6-(4-methylphenyl)thiopyridine (0.50 g, 2.2 mmol), triethylamine(0.46 ml, 3.3 mmol) and toluene (30 ml) was refluxed for 48 hrs asdescribed in Example 1. The solvent was concentrated under reducedpressure. The residue was recrystallized from ethanol to give the titledcompound (0.10 g, 13%) as crystals.

mp. 176.9-178.4° C.

IR(KBr): 1660, 1651, 1568, 1556, 1529, 1431, 1292, 1234, 1095, 964, 912,742 cm⁻¹.

¹H-NMR(CDCl₃) δ: 2.45 (3H, s), 7.08-7.11 (1H, m), 7.31 (2H, d, J=8.0Hz), 7.57-7.67 (6H, m), 8.17-8.20 (1H, m), 8.51-8.54 (1H, m).

Elemental Analysis for C₂₀H₁₄N₂OS₂

Calcd. C, 66.27; H, 3.89; N, 7.73.

Found C, 66.00; H, 3.83; N, 7.68.

Example 47

[5-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methyl acetate

A mixture of methyl thiosalicylate (0.58 g, 3.43 mmol), a mixture of5-acetoxy-2-cyanopyridine and 3-acetoxy-2-cyanopyridine (0.60 g, 3.43mmol), triethylamine (0.72 ml, 5.15 mmol) and toluene (100 ml) wasrefluxed for 48 hrs as described in Example 1. The solvent wasconcentrated under reduced pressure. The residue was recrystallized fromethanol to give the titled compound (0.30 g, 29%) as crystals.

mp. 171.4-171.5° C.

IR(KBr): 1730, 1649, 1537, 1267, 1053, 852, 736 cm⁻¹.

¹H-NMR(CDCl₃) δ: 2.15 (3H, s), 5.23 (2H, s), 7.60-7.70 (3H, m),7.89-7.92 (1H, m), 8.54-8.57 (1H, m), 8.72 (1H, d, J=1.7 Hz)

Elemental Analysis for C₁₆H₁₂N₂O₃S

Calcd. C, 61.53; H, 3.87; N, 8.97.

Found C, 61.56; H, 3.99; N, 9.01.

Example 48

2-[5-(hydroxymethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one

[5-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methyl acetate (0.16 g,0.5 mmol) obtained in Example 47, potassium carbonate (0.002 g, 0.02mmol) and methanol (30 ml) was stirred under nitrogen atmosphere at roomtemperature for 2 hrs. The reaction mixture was concentrated underreduced pressure, dissolved in hot ethanol and filtered. The filtratewas concentrated under reduced pressure and recrystallized from ethanolto give the titled compound (0.10 g, 74%) as crystals.

mp. 246.9-247.9° C.

IR(Neat): 3414, 1631, 1589, 1568, 1520, 1317, 1053, 738 cm⁻¹.

¹H-NMR(CDCl₃) δ: 3.50 (1H, br s), 4.89 (2H, d, J=5.7 Hz), 7.60-7.69 (3H,m), 7.92-7.95 (1H, m), 8.53-8.57 (2H, m), 8.73 (1H, s).

Elemental Analysis for C₁₄H₁₀N₂O₂S

Calcd. C, 62.21; H, 3.73; N, 10.36.

Found C, 62.23; H, 3.68; N, 10.34.

Example 49

2-[5-(trifluoromethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-on e

A mixture of methyl thiosalicylate (0.43 g, 2.6 mmol),2-cyano-5-trifluoromethylpyridine (0.44 g, 2.6 mmol), triethylamine(0.60 ml, 3.8 mmol) and toluene (30 ml) was refluxed for 48 hrs asdescribed in Example 1. The solvent was concentrated under reducedpressure. The residue was recrystallized from ethanol to give the titledcompound (0.18 g, 23%) as crystals.

mp. 207.2-207.4° C.

IR(KBr): 1653, 1568, 1525, 1327, 1305, 1122, 1074, 1012, 939, 871, 742cm⁻¹.

¹H-NMR(CDCl₃) δ: 7.63-7.73 (3H, m), 8.16-8.18 (1H, m), 8.55-8.58 (1H,m), 8.68 (1H, d, J=8.3 Hz), 9.00 (1H, s).

Elemental Analysis for C₁₄H₇N₂OSF₃

Calcd. C, 54.54; H, 2.29; N, 9.09.

Found C, 54.68; H, 2.32; N, 9.26.

Example 50

6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-N-propyl-2-pyridinecarbo xamide

A mixture of methyl thiosalicylate (4.2 g, 25 mmol),6-cyano-N-propyl-2-pyridinecarboxamide (2.5 g, 13 mmol), triethylamine(4.0 ml, 28 mmol) and toluene (8 ml) was refluxed for 8 hrs as describedin Example 1. After cooling, the precipitated crystals were collected byfiltration and recrystallized from hexane-tetrahydrofuran to give thetitled compound (3.4 g, 78%) as crystals.

mp. 179.7-181.4° C.

IR (KBr): 3400, 2962, 2872, 1666, 1572, 1537, 1440, 1300, 1232, 1095,746, 733 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.08 (3H, t, J=7.4 Hz), 1.78 (2H, m), 3.55 (2H, m),7.62-7.74 (3H, m), 7.96 (1H, br s), 8.08 (1H, m), 8.44 (1H, d, J=7.7Hz), 8.56 (1H, m), 8.65 (1H, d, J=7.8 Hz).

Elemental Analysis for C₁₇H₁₅N₃O₂S

Calcd. C, 62.75; H, 4.65; N, 12.91.

Found C, 62.76; H, 4.65; N, 12.93.

Example 51

N-Benzyl-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridinecarbo xamide

A mixture of methyl thiosalicylate (1.3 g, 7.6 mmol),N-benzyl-6-cyano-2-pyridinecarboxamide (0.88 g, 3.7 mmol), triethylamine(2.0 ml, 14 mmol) and toluene (4 ml) was refluxed for 10 hrs asdescribed in Example 1. After cooling, the precipitated crystals werecollected by filtration and recrystallized from hexane-tetrahydrofuranto give the titled compound (0.97 g, 97%) as crystals.

mp. 197.1-197.9° C.

IR (KBr): 400, 3061, 1669, 1572, 1535, 1440, 1300, 1232, 1097, 746, 733cm⁻¹.

¹H-NMR (CDCl₃) δ: 4.80 (2H, d, J=6.2 Hz), 7.32-7.46 (5H, m) 7.57-7.69(3H, m), 8.10 (1H, m), 8.26 (1H, m), 8.48 (1H, d, J=7.7 Hz), 8.55 (1H,d, J=7.5 Hz), 8.66 (1H, d, J=7.8 Hz).

Elemental Analysis for C₂₁H₁₅N₃O₂S

Calcd. C, 67.54; H, 4.05; N, 11.25.

Found C, 67.47; H, 3.91; N, 11.21.

Example 52

N,N-Dimethyl-N′-[[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]carbonyl]-N′-propylurea

A mixture of methyl thiosalicylate (1.6 g, 9.6 mmol),N-[(6-cyano-2-pyridyl)carbonyl]-N′,N′-dimethyl-N-propylurea (1.2 g, 4.7mmol), triethylamine (2.0 ml, 14 mmol) and toluene (4 ml) was refluxedfor 9 hrs as described in Example 1. After cooling, the precipitatedcrystals were collected by filtration and recrystallized fromhexane-tetrahydrofuran to give the titled compound (1.36 g, 72%) ascrystals.

mp. 190.8-192.4° C.

IR (KBr): 2962, 1682, 1666, 1537, 1379, 1305, 1126, 750, 731 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.01 (3H, t, J=7.4 Hz), 1.78 (2H, m), 2.98 (6H, s),3.77 (2H, m), 7.61-7.71 (3H, m), 8.04 (1H, m), 8.18 (1H, d, J=7.6 Hz),8.56 (1H, m), 8.62 (1H, m).

Elemental Analysis for C₂₀H₂₀N₄O₃S

Calcd. C, 60.59; H, 5.08; N, 14.13.

Found C, 60.54; H, 5.15; N, 14.23.

Example 53

N-Benzyl-N′,N′-dimethyl-N-[[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]carbonyl]urea

A mixture of methyl thiosalicylate (1.8 g, 10.7 mmol),N-benzyl-N-[(6-cyano-2-pyridyl)carbonyl]-N′,N′-dimethylurea (1.6 g, 5.4mmol), triethylamine (2.0 ml, 14 mmol) and toluene (4 ml) was refluxedfor 8 hrs as described in Example 1. After cooling, the precipitatedcrystals were collected by filtration and recrystallized fromhexane-chlorobenzene to give the titled compound (2.2 g, 93%) ascrystals.

mp. 222.2-224.0° C.

IR (KBr): 2947, 1678, 1666, 1537, 1373, 1302, 1234, 1165, 1095, 733cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.70 (6H, br s), 5.08 (2H, s), 7.29-7.37 (3H, m),7.47-7.49 (2H, m), 7.64-7.71 (3H, m), 8.04 (1H, m), 8.20 (1H, m), 8.55(1H, m), 8.65 (1H, m)

Elemental Analysis for C₂₄H₂₀N₄O₃S

Calcd. C, 64.85; H, 4.54; N, 12.60.

Found C, 64.77; H, 4.49; N, 12.57.

Example 54

7-methoxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of 2-mercapto-4-methoxybenzoic acid (1.4 g, 7.9 mmol),2-cyanopyridine (0.89 g, 8.5 mmol) and pyridine (10 ml) was refluxed for10 hrs as described in Example 9. After cooling, the precipitatedcrystals were collected by filtration and recrystallized fromhexane-tetrahydrofuran to give the titled compound (1.0 g, 47%) ascrystals.

mp. 200.0-202.2° C.

IR (KBr): 1643, 1603, 1566, 1487, 1278, 1251, 1020, 796 cm⁻¹.

¹H-NMR (CDCl₃) δ: 3.93 (3H, s), 7.01 (1H, d, J=2.4 Hz), 7.16 (1H, dd,J=2.4, 8.9 Hz), 7.52 (1H, m), 7.90 (1H, m), 8.49 (1H, d, J=8.9 Hz), 8.53(1H, dd, J=0.9, 7.9 Hz), 8.72 (1H, dd, J=0.7, 4.7 Hz).

Elemental Analysis for C₁₄H₁₀N₂O₂S

Calcd. C, 62.21; H, 3.73; N, 10.36.

Found C, 62.28; H, 3.61; N, 10.41.

Example 55

2-(4-Pyridyl)-4H-1,3-benzothiazine-4-one N-oxide

2-(4-pyridyl)-4H-1,3-benzothiazine-4-one (1.00 g, 4.1 mmol) wasdissolved in chloroform (20 ml). To the mixture was added3-chloroperbenzoic acid (ca. 77%, 0.92 g, 4.1 mmol). The reactionmixture was stirred at room temperature for 24 hr and concentrated underreduced pressure. The residue was subjected to a silica gel columnchromatography and eluted with ethyl acetate-methanol (20:1, v/v) andrecrystallized from diisopropylether-methanol to give the titledcompound (0.18 g, 16%) as crystals.

mp. 248.2-251.7° C.

IR (KBr): 3115, 1658, 1610, 1514, 1479, 1440, 1304, 1277, 1244, 1167,1091, 842, 750 cm⁻¹.

¹H-NMR (DMSO-d₆) δ: 7.75 (1H, m), 7.83-7.91 (2H, m), 8.12 (2H, d, J=6.4Hz), 8.35 (1H, d, J=7.8 Hz), 8.41 (2H, d, J=6.4 Hz).

Elemental Analysis for C₁₃H₈N₂O₂S

Calcd. C, 60.93; H, 3.15; N, 10.93.

Found C, 60.85; H, 3.08; N, 10.96.

Example 56

2-(6-Methoxy-2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (0.56 g, 3.4 mmol),2-cyano-6-methoxypyridine (0.45 g, 3.4 mmol), triethylamine (0.70 ml,5.0 mmol) and toluene (50 ml) was refluxed for 48 hrs as described inExample 1. The reaction mixture was concentrated under reduced pressureand recrystallized from ethanol to give the titled compound (0.12 g,13%) as crystals.

mp. 226.0-226.1° C.

IR(KBr): 1649, 1529, 1469, 1273, 1244, 1149, 1097, 1033, 808, 725 cm⁻¹.

¹H-NMR(CDCl₃) δ: 4.10 (3H, s), 7.00 (1H, d, J=8.3 Hz), 7.59-7.68 (3H,m), 7.74-7.79 (1H, m), 8.13-8.16 (1H, m), 8.54-8.57 (1H, m).

Elemental Analysis for C₁₄H₁₀N₂O₂S

Calcd. C, 62.21; H, 3.73; N, 10.36.

Found C, 62.12; H, 3.73; N, 10.44.

Example 57

2-[6-(Benzyloxy)-2-pyridyl]-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (0.40 g, 2.4 mmol),2-benzyloxy-6-cyanopyridine (0.50 g, 2.4 mmol), triethylamine (0.50 ml,3.6 mmol) and toluene (30 ml) was refluxed for 48 hrs as described inExample 1. The reaction mixture was concentrated under reduced pressureand recrystallized from ethanol to give the titled compound (0.21 g,26%) as crystals.

mp. 240.9-241.0° C.

IR(KBr): 1637, 1572, 1529, 1504, 1442, 1256, 1128, 1097, 1030, 808, 760cm⁻¹.

¹H-NMR(CDCl₃) δ: 5.55 (2H, s), 7.05 (1H, d, J=8.3 Hz), 7.34-7.43 (3H,m), 7.55 (2H, d, J=6.9 Hz), 7.62-7.69 (3H, m), 7.78 (1H, t, J=8.0 Hz),8.16 (1H, d, J=7.4 Hz), 8.54-8.57 (1H, m).

Elemental Analysis for C₂₀H₁₄N₂O₂S

Calcd. C, 69.35; H, 4.07; N, 8.09.

Found C, 69.14; H, 3.99; N, 8.13.

Example 58

2-(6-Propoxy-2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (0.24 g, 1.4 mmol),2-cyano-6-propoxypyridine (0.23 g, 1.4 mmol), triethylamine (0.30 ml,2.1 mmol) and toluene (20 ml) was refluxed for 48 hrs as described inExample 1. The reaction mixture was concentrated under reduced pressure.The residue was subjected to a silica gel column chromatography, elutedwith hexane-ethyl acetate (5:1, v/v) and recrystallized fromhexane-ethyl acetate to give the titled compound (0.03 g, 7%) ascrystals.

mp. 138.3-140.0° C.

IR (KBr): 1651, 1595, 1574, 1537, 1446, 1294, 1277, 1238, 1028, 810,740, 727 cm⁻¹.

¹H-NMR(CDCl₃) δ: 1.10 (3H, t, J=7.4 Hz), 1.86-1.95 (2H, m), 4.43 (2H, t,J=6.6 Hz), 6.97 (1H, d, J=8.2 Hz), 7.62-7.77 (4H, m), 8.12 (1H, d, J=7.3Hz), 8.53-8.56 (1H, m)

Elemental Analysis for C₁₆H₁₄N₂O₂S

Calcd. C, 64.41; H, 4.73; N, 9.39.

Found C, 64.20; H, 4.72; N, 9.43.

Example 59

2-(6-Propylthio-2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (0.67 g, 4.0 mmol),2-cyano-6-propylthiopyridine (0.72 g, 4.0 mmol), triethylamine (0.84 ml,6.0 mmol) and toluene (50 ml) was refluxed for 48 hrs as described inExample 1. The reaction mixture was concentrated under reduced pressureand the residue was recrystallized from ethanol to give the titledcompound (0.46 g, 37%) as crystals.

mp. 124.5-125.1° C.

IR (KBr): 1658, 1572, 1537, 1433, 1284, 1230, 1149, 1095, 985, 742 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.14 (3H, t, J=7.3 Hz), 1.82-1.94 (2H, m), 3.30 (2H,t, J=7.1 Hz), 7.36-7.39 (1H, m), 7.55-7.88 (4H, m), 8.19 (1H, d, J=7.6Hz), 8.54-8.57 (1H, m).

Elemental Analysis for C₁₆H₁₄N₂OS₂

Calcd. C, 61.12; H, 4.49; N, 8.91.

Found C, 60.72; H, 4.22; N, 9.05.

Example 60

2-(6-Propylsulfinyl-2-pyridyl)-4H-1,3-benzothiazine-4-one

A solution of 3-chloroperbenzoic acid (ca. 50%, 0.17 g, 0.49 mmol) inethyl acetate (20 ml) was added dropwise to a solution of

2-(6-propylthio-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.15 g, 0.48mmol), which was obtained in Example 59, in ethyl acetate (50 ml) withstirring. The reaction mixture was stirred at room temperature for 18hrs, washed with saturated aqueous sodium hydrogen carbonate solution(50 ml×2) and saturated brine, dried (MgSO₄) and concentrated underreduced pressure. The residue was recrystallized from ethyl acetate togive the titled compound (0.12 g, 76%) as crystals.

mp. 174.8-175.4° C.

IR (KBr): 1653, 1570, 1533, 1437, 1298, 1057, 1041, 1030, 733 cm⁻¹.

¹H-NMR(CDCl₃) δ: 1.11 (3H, t, J=7.4 Hz), 1.60-1.73 (1H, m) 1.97-2.04(1H, m), 2.96-3.05 (1H, m), 3.15-3.25 (1H, m), 7.61-7.74 (3H, m), 8.16(3H, t, J=7.8 Hz), 8.25 (1H, d, J=7.7 Hz), 8.55-8.60 (1H, m).

Elemental Analysis for C₁₆H₁₄N₂O₂S₂

Calcd. C, 58.16; H, 4.27; N, 8.48.

Found C, 58.17; H, 4.47; N, 8.62.

Example 61

2-(6-Propylsulfonyl-2-pyridyl)-4H-1,3-benzothiazine-4-one

A solution of 3-chloroperbenzoic acid (ca. 50%, 0.44 g, 1.2 mmol) inethyl acetate (10 ml) was added dropwise to a solution of

2-(6-propylsulfinyl-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.20 g, 0.64mmol), which was obtained in Example 60, in ethyl acetate (50 ml) withstirring. The reaction mixture was stirred at room temperature for 18hrs, washed with saturated aqueous sodium hydrogen carbonate solution(50 ml×2) and saturated brine, dried (MgSO₄) and concentrated underreduced pressure. The residue was recrystallized from ethanol to givethe titled compound (0.09 g, 41%) as crystals.

mp. 173.8-174.5° C.

IR (KBr): 1662, 1570, 1533, 1439, 1298, 1120, 1095, 1062, 993, 733 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.10 (3H, t, J=7.4 Hz), 1.86-1.96 (2H, m), 3.49-3.52(2H, m), 7.66-7.74 (3H, m), 8.21 (3H, t, J=7.8 Hz), 8.30-8.33 (1H, m),8.56-8.58 (1H, m), 8.58-8.78 (1H, m).

Elemental Analysis for C₁₆H₁₄N₂O₃S₂

Calcd. C, 55.47; H, 4.07; N, 8.09.

Found C, 55.44; H, 3.84; N, 8.04.

Example 62

2-[6-(4-Phenyl-1-piperazinyl)-2-pyridyl]-4H-1,3-benzothiazi ne-4-one

A mixture of methyl thiosalicylate (0.25 g, 1.5 mmol),2-cyano-6-(4-phenyl-1-piperazinyl)pyridine (0.40 g, 1.5 mmol)triethylamine (0.32 ml, 2.3 mmol) and toluene (30 ml) was refluxed for48 hrs. The reaction mixture was concentrated under reduced pressure andthe crude crystals were recrystallized from ethanol to give the titledcompound (0.20 g, 33%) as crystals.

mp. 245.8° C. (decomposed).

IR (KBr): 1655, 1593, 1535, 1444, 1232, 1095, 1006, 937, 746 cm⁻¹.

¹H-NMR (CDCl₃) δ: 3.36-3.40 (4H, m), 3.83-3.92 (4H, m), 6.92-6.95 (2H,m), 7.00-7.02 (2H, m), 7.29-7.34 (2H, m), 7.60-7.71 (4H, m), 7.88 (1H,d, J=7.3 Hz), 8.53-8.56 (1H, m)

Elemental Analysis for C₂₃H₂₀N₄OS

Calcd. C, 68.98; H, 5.03; N, 13.99.

Found C, 68.66; H, 4.95; N, 13.83.

Example 63

2-{6-[(4-Methylphenyl)sulfinyl]-2-pyridyl}-4H-1,3-benzothia zine-4-one

A solution of 3-chloroperbenzoic acid (ca. 70%, 0.27 g, 1.1 mmol) inchloroform (10 ml) was added dropwise to a solution of

2-[6-(4-methylphenylthio-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.40 g,1.1 mmol), which was obtained in Example 46, in chloroform (50 ml) withstirring. The reaction mixture was stirred at room temperature for 3 hrsand concentrated under reduced pressure. The residue was subjected to asilica gel column chromatography, eluted with hexane-ethyl acetate (2:1,v/v) and recrystallized from ethanol to give the titled compound (0.23g, 54%) as crystals.

mp. 228.0-228.2° C.

IR (KBr): 1660, 1570, 1533, 1437, 1298, 1049, 1030, 991, 733 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.36 (3H, s), 7.30 (2H, d, J=8.2 Hz), 7.65-7.67 (3H,m), 7.69 (2H, d, J=8.4 Hz), 8.08 (1H, t, J=7.9 Hz), 8.25-8.28 (1H, m),8.49-8.53 (1H m).

Elemental Analysis for C₂₀H₁₄N₂O₂S₂

Calcd. C, 63.47; H, 3.73; N, 7.40.

Found C, 63.33; H, 4.02; N, 7.40.

Example 64

2-{6-[(4-Methylphenyl)sulfonyl]-2-pyridyl)-4H-1,3-benzothia zine-4-one

A solution of 3-chloroperbenzoic acid (ca. 70%, 0.53 g, 2.1 mmol) inchloroform (10 ml) was added dropwise to a solution of

2-{6-[(4-methylphenyl)sulfinyl]-2-pyridyl}-4H-1,3-benzothia zine-4-one(0.35 g, 11.0 mmol) in chloroform (50 ml) with stirring. The reactionmixture was stirred at room temperature for 5 hrs and concentrated underreduced pressure. The residue was subjected to a silica gel columnchromatography, eluted with hexane-ethyl acetate (1:1, v/v) andrecrystallized from ethanol to give the titled compound (0.25 g, 64%) ascrystals.

mp. 219.6° C. (decomposed).

IR (KBr): 1660, 1645, 1570, 1533, 1437, 1300, 1170, 1032, 746 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.44 (3H, s), 7.40 (2H, d, J=8.2 Hz), 7.63-7.73 (3H,m), 8.06-8.15 (3H, m), 8.35-8.38 (1H, m), 8.52-8.55 (1H, m), 8.62-8.65(1H, m).

Elemental Analysis for C₂₀H₁₄N₂O₃S₂

Calcd. C, 60.90; H, 3.58; N, 7.10.

Found C, 60.78; H, 3.71; N, 7.03.

Example 65

2-[(6-Methoxymethoxymethyl)-2-pyridyl]-4H-1,3-benzothiazine -4-one

Chloromethyl methylether (0.40 g, 5.0 mmol) was added dropwise to amixture of 2-(6-hydroxymethyl-2-pyridyl)-4H-1,3-benzothiazine-4-one(0.13 g, 0.5 mmol) obtained in Example 40 and diisopropylamine (3 ml) atroom temperature. The reaction mixture was stirred for 18 hrs, dilutedwith water and extracted with ethyl acetate (100 ml×2). The extract waswashed with 5% HCl (100 ml×2) and saturated brine, dried (MgSO₄) andconcentrated under reduced pressure. The residue was subjected to asilica gel column chromatography, eluted with hexane-ethyl acetate (1:1,v/v) and recrystallized from ethanol to give the titled compound (0.29g, 58%) as crystals.

mp. 159.6-159.8° C.

IR (KBr): 1658, 1572, 1531, 1437, 1298, 1269, 1232, 1093, 1053, 912,802, 738 cm⁻¹.

¹H-NMR (CDCl₃) δ: 3.46 (3H, s), 4.84 (4H, s), 7.59-7.72 (4H, m), 7.92(1H, t, J=7.8 Hz), 8.44 (1H, d, J=7.8 Hz), 8.52-8.57 (1H, m).

Elemental Analysis for C₁₆H₁₄N₂O₃S

Calcd. C, 61.13; H, 4.49; N, 8.91.

Found C, 60.88; H, 4.48; N, 8.61.

Example 66

tert-Butyl

3-{3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propoxy} propanoate

Methyl thiosalicylate (1.0 g, 6.1 mmol) and tert-butyl3-[3-(6-cyano-2-pyridyl)propoxy]propanoate (1.6 g, 5.5 mmol) weredissolved in toluene (5.0 ml). Triethylamine (1.35 ml, 9.7 mmol) wasadded to the mixture and the mixture was refluxed for 14 hrs. Thereaction mixture was subjected to a silica gel (110 g) columnchromatography and eluted with hexane-ethyl acetate (3:2, v/v) to givethe titled compound (1.7 g, 67%) as white crystals.

mp. 71.0-71.9° C.

IR(KBr): 1728, 1664, 1572, 1537, 1159 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.14 (2H, m), 2.51 (2H, t, J=6.3 Hz),2.99 (2H, t, J=7.2 Hz), 3.57 (2H, t, J=6.3 Hz), 3.71 (2H, t, J=6.3 Hz),7.39 (1H, d, J=7.5 Hz), 7.59-7.71 (3H, m), 7.79 (1H, t, J=7.8 Hz), 8.35(1H, d, J=7.8 Hz), 8.55 (1H, d, J=7.8 Hz).

Elemental Analysis for C₂₃H₂₆N₂O₄S

Calcd. C, 64.77; H, 6.14; N, 6.57.

Found C, 64.51; H, 6.01; N, 6.50.

Example 67

3-{3-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propoxy}propionicacid

tert-Butyl 3-{3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propoxy}propanoate (1.70 g, 4.0 mmol) was dissolved in trifluoroacetic acid (15ml) under ice cooling, and the mixture was stirred at 0° C. for 5 hrs.The reaction mixture was combined with isopropylether (50 ml) andstirred for 30 minutes. The precipitated crystals were collected byfiltration. The crystals were recrystallized from ethanol-hexane to givethe titled compound (0.57 g, 39%) as white crystals.

mp. 141.0-142.0° C.

IR(KBr): 3061, 1732, 1658, 1572, 1529, 1305 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.15 (2H, m), 2.66 (2H, t, J=6.2 Hz), 2.98 (2H, t,J=7.5 Hz), 3.59 (2H, t, J=6.3 Hz), 3.75 (2H, t, J=6.2 Hz), 7.37 (1H, d,J=7.5 Hz), 7.59-7.71 (3H, m), 7.79 (1H, t, J=7.8 Hz), 8.34 (1H, d, J=7.8Hz), 8.54 (1H, d, J=7.8 Hz).

Elemental Analysis for C₁₉H₁₈N₂O₄S

Calcd. C, 61.61; H, 4.90; N, 7.56.

Found C, 61.47; H, 4.94; N, 7.36.

Example 68

2-(2-Mehtylthio-4-pyridyl)-4H-1,3-benzothiazine-4-one

Methyl thiosalicylate (0.76 g, 4.5 mmol) and2-methylthioisonicotinonitrile (0.34 g, 2.3 mmol) were dissolved intoluene (2.0 ml). Triethylamine (0.70 ml, 5.0 mmol) was added theretoand the mixture was refluxed for 6 hrs. The reaction mixture was cooledat room temperature and the precipitated crystals were collected andrecrystallized from ethanol to give the titled compound (0.11 g, 17%) aswhite crystals.

mp. 173.4-173.5° C.

IR(KBr): 1655, 1585, 1520, 1361, 1294 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.59 (3H, s), 7.56-7.73 (4H, m), 7.91 (1H, s), 8.56(1H, dd, J=7.5, 1.8 Hz), 8.63 (1H, d, J=5.3 Hz).

Elemental Analysis for C₁₄H₁₀N₂OS₂

Calcd. C, 58.72; H, 3.52; N, 9.78.

Found C, 58.72; H, 3.47; N, 9.88.

Reference Example 5

2-Benzyloxyisonicotinonitrile

Sodium hydride (60% oil, 0.13 g, 3.3 mmol) was suspended intetrahydrofuran (2 ml), Benzyl alcohol (0.30 g, 3.2 mmol) was addedthereto and the mixture was stirred for 30 minutes.

A solution of 2-chloro-4-cyanopyridine (0.40 g, 2.9 mmol) intetrahydrofuran (1 ml) was added to the mixture and the mixture wasrefluxed for 6 hrs. The reaction mixture was combined with ethyl acetateand water and stirred. The organic layer was washed with saturated brineand dried over anhydrous magnesium sulfate. The solvent was evaporated.The residue was subjected to a silica gel (30 g) column chromatography,eluted with hexane-ethyl acetate (4:1, v/v) to give the titled compound(0.37 g, 62%).

¹H-NMR (CDCl₃) δ: 5.41 (2H, m), 7.04-7.09 (2H, m), 7.33-7.45 (5H, m),8.31 (1H, d, J=4.8 Hz).

Example 69

2-(2-Benzyloxy-4-pyridyl)-4H-1,3-benzothiazine-4-one

Methyl thiosalicylate (0.59 g, 3.5 mmol) and2-(benzyloxy)isonicotinonitrile (0.37 g, 1.8 mmol) were dissolved intoluene (2.0 ml). Triethylamine (0.54 ml, 3.9 mmol) was added theretoand the mixture was refluxed for 6 hrs. The reaction mixture wassubjected to a silica gel (50 g) column chromatography, eluted withhexane-ethyl acetate (2:1, v/v) and recrystallized from ethanol to givethe titled compound (0.20 g, 32%) as white crystals.

mp. 116.0-116.5° C.

IR(KBr): 1665, 1603, 1529, 1410, 1354, 1288 cm⁻¹.

¹H-NMR (CDCl₃) δ: 5.46 (2H, s), 7.35-7.70 (10H, m), 8.36 (1H, d, J=5.4Hz), 8.56 (1H, dd, J=7.5, 1.8 Hz).

Elemental Analysis for C₂₀H₁₄N₂O₂S

Calcd. C, 69.35; H, 4.07; N, 8.09.

Found C, 69.21; H, 4.26; N; 8.09.

Example 70

2-(2-Methoxy-4-pyridyl)-4H-1,3-benzothiazine-4-one

2-Chloro-4-cyanopyridine (0.40 g, 2.9 mmol) was dissolved intetrahydrofuran (1 ml), and 12% lithium methylate in methanol (1.0 g,3.2 mmol) was added thereto. The reaction mixture was refluxed for 6hrs, combined with water, extracted with ethyl acetate, washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure to give a mixture (0.30 g)containing 2-methoxyisonicotinonitrile. This mixture and methylthiosalicylate (1.0 g, 5.9 mmol) were dissolved in toluene (3.0 ml), andtriethylamine (1.0 ml, 7.2 mmol) was added thereto. The reaction mixturewas refluxed for 8 hrs, subjected to a silica gel (60 g) columnchromatography, eluted with hexane-ethyl acetate (2:1, v/v) to give thetitled compound (0.05 g, 8%) as white crystals.

mp. 148.8-150.5° C.

IR(KBr): 1662, 1525, 1448, 1387, 1315 cm⁻¹.

¹H-NMR (CDCl₃) δ: 4.01 (3H, s), 7.46 (1H, s), 7.56-7.74 (4H, m) 8.35(1H, d, J=5.4 Hz), 8.56 (1H, dd, J=7.5, 1.8 Hz).

Elemental Analysis for C₁₄H₁₀N₂O₂S

Calcd. C, 62.21; H, 3.73; N, 10.36.

Found C, 61.95; H, 3.49; N, 10.17.

Reference Example 6

2-[N-Benzyl-N-methylamino]isonicotinonitrile

2-Chloro-4-cyanopyridine (0.40 g, 2.9 mmol) was dissolved inN-methylpyrrolidone (2.0 ml), and N-methyl-N-benzylamine (1.0 ml, 7.8mmol) was added thereto. The reaction mixture was stirred at 100° C. for2.5 hrs, combined with water, extracted with ethyl acetate, washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was subjected to asilica gel (50 g) column chromatography, eluted with hexane-ethylacetate (3:1, v/v) to give the titled compound (0.47 g, 72%).

¹H-NMR (CDCl₃) δ: 3.09 (3H, s), 4.82 (2H, s), 6.67 (1H, s), 6.72 (1H, d,J=5.0 Hz), 7.08-7.35 (5H, m), 8.28 (1H, d, J=5.0 Hz).

Example 71

2-[2-(N-Benzyl-N-methylamino)-4-pyridyl]-4H-1,3-banzothiazi ne-4-one

Methyl thiosalicylate (0.70 g, 4.2 mmol) and2-[N-benzyl-N-methylamino]isonicotinonitrile (0.46 g, 2.1 mmol) weredissolved in toluene (2.0 ml), and triethylamine (0.68 ml, 4.9 mmol) wasadded thereto. The reaction mixture was refluxed for 8 hrs, subjected tosilica gel (50 g) column chromatography, eluted withhexane-ethyl-acetate (2:1, v/v) and recrystallized from ethanol to givethe titled compound (0.23 g, 15%)

mp. 145.9-146.6° C.

IR(KBr): 1662, 1597, 1525, 1494, 1412, 1290 cm⁻¹.

¹H-NMR (CDCl₃) δ: 3.14 (3H, s), 4.92 (2H, s), 7.17-7.26 (7H, m)7.56-7.70 (3H, m), 8.34 (1H, d, J=5.2 Hz), 8.55 (1H, dd, J=7.7, 1.8 Hz).

Elemental Analysis for C₂₁H₁₇N₃OS

Calcd. C, 70.17; H, 4.77; N, 11.69.

Found C, 69.92; H, 4.65; N, 11.70.

Reference Example 7

2-(Hexylamino)isonicotinonitrile

2-Chloro-4-cyanopyridine (0.40 g, 2.9 mmol) was dissolved inN-methylpyrrolidone (2.0 ml), and hexylamine (1.15 ml, 8.7 mmol) wasadded thereto. The reaction mixture was stirred at 100° C. for 4 hrs,combined with water, extracted with ethyl acetate, washed with saturatedbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was subjected to a silicagel (50 g) column chromatography, eluted with hexane-ethyl acetate (3:1,v/v) to give the titled compound (0.26 g, 46%).

¹H-NMR (CDCl₃) δ: 0.90 (3H, t, J=6.9 Hz), 1.29-1.44 (6H, m), 1.61 (2H,q, J=7.2 Hz), 3.26 (2H, q, J=6.9 Hz), 4.77 (1H, br s), 6.54 (1H, s),6.71 (1H, d, J=5.1 Hz), 8.18 (1H, d, J=5.1 Hz).

Example 72

2-[2-(Hexylamino)-4-pyridyl]-4H-1,3-benzothiazine-4-one

Methyl thiosalicylate (0.44 g, 2.6 mmol) and2-(hexylamino)isonicotinonitrile (0.26 g, 1.3 mmol) were dissolved intoluene (2.0 ml), and triethylamine (0.40 ml, 2.9 mmol) was addedthereto. The reaction mixture was refluxed for 14 hrs, subjected to asilica gel (50 g) chromatography, eluted with hexane-ethyl acetate (2:1,v/v) and recrystallized from ethanol to give the titled compound (0.08g, 18%) as white crystals.

mp. 133.8-134.6° C.

IR(KBr): 3375, 1649, 1601, 1518, 1292 cm⁻¹.

¹H-NMR (CDCl₃) δ: 0.91 (3H, t, J=6.9 Hz), 1.31-1.42 (6H, m), 1.65 (2H,q, J=7.2 Hz), 3.35 (2H, q, J=6.9 Hz), 4.74 (1H, m), 7.13 (1H, s), 7.16(1H, d, J=1.3 Hz), 7.56 (1H, d, J=7.5 Hz), 7.63-7.74 (2H, m), 8.25 (1H,d, J=5.3 Hz), 8.55 (1H, dd, J=7.5, 1.8 Hz).

Elemental Analysis for C₁₉H₂₁N₃OS

Calcd. C, 67.23; H, 6.24; N, 12.38.

Found C, 66.95; H, 6.07; N, 12.37.

Reference Example 8

2-Morpholinylisonicotinonitrile

2-Chloro-4-cyanopyridine (0.40 g, 2.9 mmol) was dissolved inN-methylpyrrolidone (2.0 ml), and morpholine (0.7 ml, 8.0 mmol) wasadded thereto. The reaction mixture was stirred at 100° C. for 2.5 hrsand combined with water to give precipitates, which were collected byfiltration and dried to give the titled compound (0.39 g, 70%).

¹H-NMR (CDCl₃) δ: 3.55 (4H, m), 3.82 (4H, m), 6.79 (1H, s), 6.80 (1H, d,J=5.7 Hz), 8.30 (1H, d, J=5.7 Hz).

Example 73

2-(2-Morpholinyl-4-pyridyl)-4H-1,3-benzothiazine-4-one

Methyl thiosalicylate (0.49 g, 2.9 mmol) and2-morpholinylisonicotinonitrile (0.38 g, 2.0 mmol) were dissolved intoluene (2.0 ml), and triethylamine (0.48 ml, 3.4 mmol) was addedthereto. The reaction mixture was refluxed for 14 hrs. After cooling,the precipitated crystals were collected by filtration andrecrystallized from ethanol. The obtained crystals were recrystallizedfrom ethyl acetate again to give the titled compound (0.16 g, 25%) aswhite crystals.

mp. 157.0-158.0° C.

IR(KBr): 1660, 1591, 1525, 1433, 1290 cm⁻¹.

¹H-NMR (CDCl₃) δ: 3.64 (4H, m), 3.84 (4H, m), 7.24 (1H, m), 7.41 (1H,s), 7.57 (1H, dd, J=7.4, 1.5 Hz), 7.70 (2H, m), 8.36 (1H, d, J=5.2 Hz),8.57 (1H, dd, J=7.5, 1.4 Hz).

Elemental Analysis for C₁₇H₁₅N₃O₂S

Calcd. C, 62.75; H, 4.65; N, 12.91.

Found C, 62.53; H, 4.47; N, 12.92.

Reference Example 9

2-[4-(4-Fluorophenyl)-1-piperazinyl]isonicotinonitrile

2-Chloro-4-cyanopyridine (0.40 g, 2.9 mmol) was dissolved inN-methylpyrrolidone (2.0 ml), and 1-(4-fluorophenyl)piperazine (1.0 g,5.6 mmol) was added thereto. The reaction mixture was stirred at 100° C.for 10 hrs, combined with water to give precipitates, which werecollected by filtration to give the titled compound (0.70 g, 86%).

¹H-NMR (CDCl₃) δ: 3.34 (4H, m), 3.74 (4H, m), 6.79 (1H, d, J=5.0 Hz),6.86 (1H, s), 6.90-7.03 (4H, m), 8.30 (1H, d, J=5.0 Hz).

Example 74

2-{2-[4-(4-Fluorophenyl)-1-piperazinyl]-4-pyridyl}-4H-1,3-benzothiazine-4-one

Methyl thiosalicylate (0.70 g, 4.2 mmol) and2-[4-(4-fluorophenyl)-1-piperazinyl]isonicotinonitrile (0.69 g, 2.4mmol) were dissolved in toluene (2.0 ml), and triethylamine (0.71 ml,5.1 mmol) was added thereto. The reaction mixture was refluxed for 17hrs and the precipitated crystals were collected by filtration. Thefiltrate was concentrated, subjected to a silica gel (50 g) columnchromatography, eluted with hexane-ethyl acetate (2:1, v/v) to givecrystals, which were combined with the previously obtained crystals andrecrystallized from acetone-ethanol to give the titled compound (0.18 g,17%) as white crystals.

mp. 233.0-233.6° C.

IR(KBr): 1661, 1593, 1523, 1508, 1435, 1290 cm¹.

¹H-NMR (CDCl₃) δ: 3.23 (4H, m), 3.84 (4H, m), 6.95-7.00 (4H, m), 7.23(1H, m), 7.48 (1H, s), 7.58-7.72 (3H, m), 8.37 (1H, d, J=5.2 Hz), 8.55(1H, dd, J=7.6, 1.8 Hz).

Elemental Analysis for C₂₃H₁₉N₄OSF

Calcd. C, 66.01; H, 4.58; N, 13.39.

Found C, 65.87; H, 4.77; N, 13.38.

Example 75

2-(2-Phenyl-4-pyridyl)-4H-1,3-benzothiazine-4-one

2-Chloro-4-cyanopyridine (0.40 g, 2.9 mmol), phenylboric acid (0.53 g,4.3 mmol) and potassium carbonate (1.0 g, 7.2 mmol) were dissolved intoluene-ethanol-water (4:1:1, 30 ml), and the mixture was deairatedunder reduced pressure for 15 minutes.Tetrakis(triphenylphosphine)palladium (0.17 g, 0.14 mmol) was added tothe mixture under nitrogen atmosphere, and the mixture was refluxed for21 hrs. The reaction mixture was combined with ethyl acetate-water. Theorganic layer was washed with saturated brine and dried over an hydrousmagnesium sulfate. The solvent was evaporated under reduced pressure togive crude 2-phenylisonicotinenitrile. Methyl thiosalicylate (1.10 g,6.5 mmol) and 2-phenylisonicotinenitrile (0.50 g, 2.8 mmol) wasdissolved in toluene (2.0 ml), and triethylamine (1.1 ml, 7.9 mmol) wasadded thereto. The reaction mixture was refluxed for 18 hrs, cooled atroom temperature to give precipitated crystals, which were collected byfiltration. The filtrate was concentrated, subjected to a silica gel (50g) column chromatography and eluted with hexane-ethyl acetate (2:1, v/v)to give crystals, which were combined with the previously obtainedcrystals and recrystallized from ethanol to give the titled compound(0.34 g, 27%) as white crystals.

mp. 162.7-163.0° C.

IR(KBr): 1665, 1591, 1525, 1286 cm⁻¹.

¹H-NMR (CDCl₃) δ: 7.49-7.74 (6H, m), 7.92 (1H, dd, J=5.1, 1.5 Hz), 8.11(2H, m), 8.47 (1H, s), 8.58 (1H, d, J=7.6 Hz), 8.91 (1H, d, J=5.1 Hz).

Elemental Analysis for C₁₉H₁₂N₂OS

Calcd. C, 72.13; H, 3.82; N, 8.85.

Found C, 71.92; H, 3.70; N, 8.69.

Reference Example 10

2-(2-Thienyl)isonicotinonitrile

2-Chloro-4-cyanopyridine (0.50 g, 3.6 mmol) and 2-thienylboric acid(0.69 g, 5.4 mmol) were dissolved in toluene-ethanol (4:1, v/v, 25 ml),and to the mixture, a solution of potassium carbonate (1.3 g, 9.0 mmol)in water (5 ml) was added. The mixture was deairated under reducedpressure for 15 minutes. Tetrakis(triphenylphosphine)palladium (0.21 mg,0.2 mmol) was added to the mixture under nitrogen atmosphere, and themixture was refluxed for 20 hrs. The reaction mixture was combined withethyl acetate and water. The organic layer was washed with saturatedbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was subjected to a silicagel (60 g) column chromatography and eluted with hexane-ethyl acetate(3:1, v/v) to give solid, which was recrystallized from ethanol to givethe titled compound (0.35 g, 52%).

¹H-NMR (CDCl₃) δ: 7.16 (1H, dd, J=5.1, 3.9 Hz), 7.34 (1H, d, J=5.1 Hz),7.49 (1H, d, J=5.1 Hz), 7.64 (1H, d, J=3.9 Hz), 8.03 (1H, s), 8.71 (1H,d, J=5.1 Hz).

Example 75

2-[2-(2-Thienyl)-4-pyridyl]-4H-1,3-benzothiazine-4-one

Methyl thiosalicylate (0.38 g, 2.2 mmol) and(2-thienyl)isonicotinonitrile (0.26 g, 1.4 mmol) were dissolved intoluene (2.0 ml), and triethylamine (0.39 ml, 2.8 mmol) was addedthereto. The reaction mixture was refluxed for 24 hrs. The reactionmixture was subjected to a silica gel (30 g) column chromatography,eluted with hexane-ethyl acetate (2:1, v/v) and recrystallized fromethanol to give the titled compound (0.22 g, 30%) as white crystals.

mp. 160.4-161.1° C.

IR(KBr): 1662, 1591, 1522, 1285 cm⁻¹.

¹H-NMR (CDCl₃) δ: 7.16 (1H, dd, J=5.0, 3.7 Hz), 7.46 (1H, m), 7.61-7.81(5H, m), 8.37 (1H, s), 8.57 (1H, m), 8.76 (1H, d, J=5.0 Hz).

Elemental Analysis for C₁₇H₁₀N₂OS₂

Calcd. C, 63.33; H, 3.13; N, 8.69.

Found C, 63.19, H, 3.19; N, 8.63.

Examples 76 and 77

2-(2-Chloro-4-pyridyl)-4H-1,3-benzothiazine-4-one and methyl2-{[4-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]thio}benzo ate

Methyl thiosalicylate (3.6 g, 21.6 mmol) and 2-chloro-4-cyanopyridine(3.0 g, 21.7 mmol) were dissolved in toluene (5.0 ml), and triethylamine(4.5 ml, 32.3 mmol) was added thereto. The reaction mixture was refluxedfor 22 hrs. The reaction mixture was subjected to a silica gel (120 g)column chromatography, eluted with hexane-ethyl acetate (1:2, v/v) andrecrystallized from acetone-ethyl acetate to give2-(2-chloro-4-pyridyl)-4H-1,3-benzothiazine-4-one (0.47 g, 8.0%) aswhite crystals.

mp. 177.8-178.4° C.

IR(KBr): 1665, 1587, 1522, 1294 cm⁻¹.

¹H-NMR (CDCl₃) δ: 7.60 (1H, m), 7.74 (2H, m), 7.94 (1H, d, J=5.1 Hz),8.10 (1H, s), 8.57 (1H, d, J=7.2 Hz), 8.62 (1H, d, J=5.1 Hz).

Elemental Analysis for C₁₃H₇N₂OSCl

Calcd. C, 56.83; H, 2.57; N, 10.20.

Found C, 56.58; H, 2.28, N, 10.19.

The fractions eluted with ethyl acetate were collected, concentrated andrecrystallized from ethyl acetate to give methyl

2-{[4-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]thio}benzo ate (0.55 g,6.0%) as white crystals.

mp. 137.0-137.9° C.

IR(KBr): 1714, 1665, 1523, 1291 cm⁻¹.

¹H-NMR (CDCl₃) δ: 3.86 (3H, s), 7.40-7.70 (6H, m), 7.81 (1H, m), 7.94(2H, m), 8.55 (1H, d, J=7.5 Hz), 8.67 (1H, d, J=5.1 Hz).

Elemental Analysis for C₂₁H₁₄N₂O₃S₂

Calcd. C, 62.05; H, 3.47; N, 6.89.

Found C, 61.88; H, 3.30; N, 6.68.

Reference Example 11

tert-Butyl (E)-3-(2-pyridyl)-2-propenoate

Sodium hydride (60% oil, 0.6 g, 15.7 mmol) was washed with hexane andsuspended in tetrahydrofuran (5 ml). To the mixture, a solution oftert-butyl diethylphosphinoacetate (2.5 g, 9.8 mmol) in tetrahydrofuran(2 ml) was added under ice cooling condition. The reaction mixture wasstirred at room temperature for 30 minutes, cooled under ice coolingcondition. A solution of 2-formylpyridine (1.0 g, 9.3 mmol) intetrahydrofuran (3.0 ml) was added to the mixture, and the mixture wasstirred at 0° C. for 1.5 hrs. The reaction mixture was combined withwater and extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was subjected to asilica gel (60 g) column chromatography, and eluted with hexane-ethylacetate (3:1, v/v) to give the titled compound (1.5 g, 77%).

¹H-NMR (CDCl₃) δ: 1.53 (9H, s), 6.82 (1H, d, J=15.7 Hz), 7.23 (1H, m),7.41 (1H, d, J=7.8 Hz), 7.59 (1H, d, J=15.7 Hz), 7.70 (1H, t, J=7.8 Hz),8.63 (1H, d, J=4.5 Hz).

Reference Example 12

tert-butyl 3-(2-pyridyl)propanoate

tert-Butyl (E)-3-(2-pyridyl)-2-propenoate (1.1 g, 5.4 mmol) wasdissolved in ethanol (12 ml), and a solution of ammonium formate (2.0 g,32.0 mmol) in water (3 ml) was added thereto. The reaction mixture wasrefluxed for 1.5 hrs, combined with ethyl acetate and water andfiltered. The filtrate was extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to give the titledcompound (1.0 g, 94%).

¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 2.70 (2H, t, J=7.6 Hz), 3.07 (2H, t,J=7.6 Hz), 7.11 (1H, m), 7.17 (1H, d, J=7.8 Hz), 7.58 (1H, t, J=7.8 Hz),8.52 (1H, d, J=4.8 Hz).

Reference Example 13

tert-Butyl 3-(1-oxido-2-pyridyl)propanoate

tert-Butyl 3-(2-pyridyl)propanoate (1.0 g, 5.0 mmol) was dissolved inethyl acetate (5 ml), and 3-chloroperbenzoic acid (ca. 70%, 1.3 g, 5.2mmol) was added thereto. The reaction mixture was subjected to a silicagel (50 g) column chromatography and eluted with ethyl acetate-ethanol(5:1, v/v) to give the titled compound (0.9 g, 80%).

¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 2.76 (2H, t, J=7.1 Hz), 3.17 (2H, t,J=7.1 Hz), 7.15-7.32 (3H, m), 8.24 (1H, d, J=5.7 Hz).

Reference Example 14

tert-Butyl 3-(6-cyano-2-pyridyl)propanoate

tert-Butyl 3-(1-oxido-2-pyridyl)propanoate (0.88 g, 3.9 mmol) wasdissolved in nitroethane (5 ml). Trimethylsilyl cyanide (0.78 g, 7.9mmol) and N,N-dimethylcarbamoyl chloride (0.85 g, 7.9 mmol) were addedthereto. The reaction mixture was stirred at room temperature for 48hrs, combined with ethyl acetate and water. The organic layer was washedsuccessively with saturated aqueous sodium hydrogen carbonate solutionand saturated brine and dried over anhydrous magnesium sulfate. Thesolvent was evaporated. The residue was subjected to a silica gel (50 g)column chromatography and eluted with hexane-ethyl acetate (3:1, v/v) togive the titled compound (0.75 g, 82%).

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 2.74 (2H, t, J=7.1 Hz), 3.12 (2H, t,J=7.1 Hz), 7.41 (1H, d, J=7.8 Hz), 7.52 (1H, d, J=7.8 Hz), 7.72 (1H, t,J=7.8 Hz).

Example 78

tert-Butyl

3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoate

tert-Butyl 3-(6-cyano-2-pyridyl)propanoate (0.74 g, 3.2 mmol) and methylthiosalicylate (1.1 g, 6.4 mmol) were dissolved in toluene (3 ml).Triethylamine (1.4 ml, 9.7 mmol) was added thereto. The reaction mixturewas refluxed for 7.5 hrs, subjected to a silica gel (75 g) columnchromatography, eluted with hexane-ethyl acetate (2:1, v/v) andrecrystallized from ethanol-hexane to give the titled compound (0.68 g,57%) as white crystals.

mp. 165.8-166.0° C.

IR(KBr): 1719, 1663, 1570, 1534, 1151 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.43 (9H, s), 2.89 (2H, t, J=7.2 Hz), 3.21 (2H, t,J=7.2 Hz), 7.42 (1H, d, J=7.7 Hz), 7.60-7.69 (3H, m), 7.80 (1H, t, J=7.7Hz), 8.36 (1H, d, J=7.6 Hz), 8.55 (1H, d, J=7.9 Hz).

Elemental Analysis for C₂₀H₂₀N₂O₃S

Calcd. C, 65.20; H, 5.47; N, 7.60.

Found C, 65.17; H, 5.31; N, 7.66.

Example 79

3-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propionic acid

tert-Butyl 3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoate(0.50 g, 1.4 mmol) was dissolved in trifluoroacetic acid (3 ml) underice cooling condition, and the mixture was stirred for 2.5 hrs. Thereaction mixture was combined with isopropylether to give theprecipitated solid, which was collected by filtration and recrystallizedfrom tetrahydrofuran-ethanol to give the titled compound (0.33 g, 77%)as white crystals.

mp. 243.2-243.5° C.

IR(KBr): 3194, 1721, 1630, 1526, 1221 cm⁻¹.

¹H-NMR (DMSO-d₆) δ: 2.82 (1H, t, J=7.2 Hz), 3.17 (1H, t, J=7.2 Hz), 7.66(1H, d, J=7.7 Hz), 7.72-7.94 (3H, m), 8.01 (1H, t, J=7.8 Hz), 8.19 (1H,d, J=7.7 Hz), 8.36 (1H, d, J=7.9 Hz), 12.18 (1H, s).

Elemental Analysis for C₁₆H₁₂N₂O₃S

Calcd. C, 61.53; H, 3.87; N, 8.97.

Found C, 61.43; H, 3.67; N, 8.95.

Reference Example 15

tert-Butyl 2-pyridinecarboxylate N-oxide

tert-Butyl 2-pyridinecarboxylate (14.0 g, 78 mmol) was dissolved inethyl acetate (200 ml), and 3-chloroperbenzoic acid (ca. 77%, 26.2 g,117 mmol) was added thereto. The reaction mixture was stirred at roomtemperature for 40 hrs. The solvent was evaporated under reducedpressure. The residue was subjected to a silica gel columnchromatography and eluted with ethyl acetate-acetone (1:1, v/v) to givethe titled compound (12.4 g, 81%).

¹H-NMR (CDCl₃) δ: 1.62 (9H, s), 7.23-7.29 (2H, m), 7.47 (1H, m) 8.20(1H, m).

Reference Example 16

tert-Butyl 6-cyano-2-pyridinecarboxylate

A mixture of tert-butyl 2-pyridinecarboxylate N-oxide (12.4 g, 63 mmol),trimethylsilyl cyanide (9.6 g, 96 mmol), N,N-dimethylcarbamoyl chloride(10.3 g, 95 mmol) and nitroethane (80 ml) was stirred at roomtemperature for 3 days. The reaction mixture was concentrated underreduced pressure. The residue was subjected to a silica gel columnchromatography, eluted with hexane-ethyl acetate (3;1, v/v) andrecrystallized from tetrahydrofuran-hexane to give the titled compound(11.1 g, 85%).

mp. 156.1-157.1° C.

IR (KBr): 3053, 2982, 2235, 1730, 1576, 1305, 1167, 993, 846, 773 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.64 (9H, s), 7.83 (1H, dd, J=1.0, 7.6 Hz), 7.98 (1H,dd, J=7.6, 8.0 Hz), 8.23 (1H, dd, J=1.0, 8.0 Hz).

Elemental Analysis for C₁₁H₁₂N₂O₂

Calcd. C, 64.69; H 5.92; N, 13.72.

Found C, 64.73; H, 5.75; N, 13.87.

Example 80

tert-Butyl 6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridinecarboxylate

A mixture of tert-butyl 6-cyano-2-pyridinecarboxylate (1.1 g, 5.3 mmol),methyl thiosalicylate (1.8 g, 10.7 mmol), triethylamine (2.0 ml, 14.3mmol) and toluene (4 ml) was refluxed for 12 hrs. After cooling, theprecipitated crystals were collected by filtration, recrystallized fromtetrahydrofuran-hexane to give the titled compound (1.3 g, 70%).

mp. 185.0-185.5° C.

IR (KBr): 2976, 1738, 1664, 1539, 1304, 1149, 742, 729 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.69 (9H, s), 7.63-7.70 (3H, m), 8.03 (1H, dd, J=7.8,7.8 Hz), 8.24 (1H, dd, J=1.0, 7.8 Hz), 8.56 (1H, m) 8.67 (1H, dd, J=1.0,7.8 Hz).

Elemental Analysis for C₁₈H₁₆N₂O₃S

Calcd. C, 63.51; H, 4.74; N, 8.23.

Found C, 63.41; H, 4.74; N, 8.10.

Example 81

6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridinecarboxylic acid

A mixture of tert-butyl6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridinecarboxylate (400 mg, 1.1mmol) and trifluoroacetic acid (10 ml) was stirred under ice coolingcondition for 3 hrs. The reaction mixture was combined withdiisopropylether to precipitate crystals, which were collected byfiltration and recrystallized from methanol-diisopropylether to give thetitled compound (245 mg, 73%).

mp. 260.2-260.5° C.

IR (KBr): 3202, 1726, 1633, 1527, 1311, 1157, 1103, 742 cm⁻¹.

¹H-NMR (DMSO-d₆) δ: 7.73 (1H, m), 7.85 (1H, m), 7.99 (1H, d, J=7.8 Hz),8.25-8.38 (3H, m), 8.53 (1H, dd, J=1.2, 7.5 Hz), 13.69 (1H, br s).

Elemental Analysis for C₁₄H₈N₂O₃S 0.5H₂O

Calcd. C, 57.33; H, 3.09; N, 9.55.

Found C, 57.39; H, 3.37; N, 9.30.

Example 82

6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-N-(2,2,2-trifluoroethyl)-2-pyridinecarboxamide

A mixture of 6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridinecarboxylicacid (350 mg, 1.2 mmol), 1-ethyl 3-(3-dimethylaminopropyl)carbodiimidehydrochloride (hereinafter abbreviated as WSC) (480 mg, 2.5 mmol),1-hydroxybenzotriazol monohydrate (hereinafter abbreviated as HOBt) (480mg, 2.5 mmol) and N,N-dimethylformamide (hereinafter abbreviated as DMF)(15 ml) was stirred at room temperature for 9 hrs. The reaction mixturewas poured into water and extracted with ethyl acetate. The extract waswashed with water and dried. The solvent was evaporated under reducedpressure. The residue was subjected to a silica gel columnchromatography, eluted with hexane-ethyl acetate (2:3, v/v) andrecrystallized from tetrahydrofuran-hexane to give the titled compound(114 mg, 25%).

mp. 242.6-244.2° C.

IR (KBr): 3404, 1691, 1664, 1537, 1290, 1267, 1167 cm⁻¹.

¹H-NMR (CDCl₃) δ: 4.23 (2H, m), 7.64-7.75 (3H, m), 8.13 (1H, m), 8.19(1H, br s), 8.45 (1H, d, J=7.7 Hz), 8.57 (1H, d, J=6.1 Hz), 8.71 (1H, d,J=7.9 Hz).

Elemental Analysis for C₁₆H₁₀N₃O₂SF₃

Calcd. C, 52.60; H, 2.76; N, 11.50.

Found C, 52.29; H, 2.64; N, 11.34.

Example 83

N-(2-Methoxyethyl)-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridinecarboxamide

A mixture of 6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridinecarboxylicacid (350 mg, 1.2 mmol), WSC (471 mg, 2.4 mmol), HOBt (332 mg, 2.4 mmol)and DMF (10 ml) was stirred at 80° C. for 17 hrs. The reaction mixturewas poured into water and extracted with ethyl acetate. The extract waswashed with water and dried. The solvent was evaporated. The residue wassubjected to a silica gel column chromatography, eluted with ethylacetate-methanol (50:1, v/v) and recrystallized fromtetrahydrofuran-hexane to give the titled compound (167 mg, 40%).

mp. 175.5-176.7° C.

IR (KBr): 3397, 2928, 1691, 1660, 1574, 1539, 1520, 1452, 1292, 1122,746 cm⁻¹.

¹H-NMR (CDCl₃) δ: 3.48 (3H, s), 3.65 (2H, t, J=4.9 Hz), 3.76 (2H, m),7.65-7.73 (3H, m), 8.09 (1H, m), 8.27 (1H, br s), 8.43 (1H, dd, J=0.9,7.7 Hz), 8.57 (1H, m), 8.66 (1H, dd, J=0.9, 7.8 Hz).

Elemental Analysis for C₁₇H₁₅N₃O₃S

Calcd. C, 59.81; H, 4.43; N, 12.31.

Found C, 59.61,; H, 4.64; N, 11.83.

Example 84

6-Hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of 5-hydroxysalicylic acid (2.0 g, 11 mmol), 2-cyanopyridine(1.2 g, 11 mmol) and pyridine (10 ml) was refluxed for 1 hr. Aftercooling, the precipitated crystals were collected by filtration andrecrystallized from dimethylsulfoxide-ethyl acetate-diethylether to givethe titled compound (1.08 g, 36%)

mp. 313.3-315.0° C.

IR (KBr): 3148, 1618, 1525, 1477, 1332, 1240, 1059, 792 cm⁻¹.

¹H-NMR (DMSO-d₆) δ: 7.30 (1H, dd, J=2.7, 8.7 Hz), 7.71-7.78 (3H, m),8.10 (1H, m), 8.34 (1H, d, J=7.9 Hz), 8.78 (1H, m), 10.43 (1H, s).

Elemental Analysis for C₁₃H₈N₂O₂S

Calcd. C, 60.93; H, 3.15; N, 10.93.

Found C, 60.75; H, 3.05; N, 10.74.

Reference Example 17

4-Trifluoromethylthiosalicylic acid

A mixture of 2-amino-4-trifluoromethylbenzoic acid (5.0 g, 24 mmol),sodium hydroxide (1.0 g, 25 mmol), sodium nitrite (1.7 g, 24 mmol) andwater (40 ml) was added dropwise to a mixture of concentratedhydrochloric acid (10 ml) and ice (10 g) while the reaction temperaturehad been kept at 0 to 5° C. The reaction mixture was stirred at the sametemperature for 30 minutes, neutralized with potassium acetate and addedto a solution of potassium O-ethyl dithocarbonate (11.7 g, 73 mmol) inwater (40 ml). The reaction mixture was stirred at 80° C. for 20 minutesand acidified by use of concentrated hydrochloric acid to pH 3. Thewater layer was separated, and the oily substance was added to 10%aqueous sodium hydroxide solution (25 g) and stirred at 80° C. for 2hrs. Sodium hydrosulfite (3 g) was added to the mixture, and the mixturewas stirred at 80° C. for 10 minutes. The reaction mixture was filteredand the filtrate was cooled and acidified by use of concentratedhydrochloric acid to pH 4. The precipitated crystals were collected byfiltration, dissolved in methanol (5 ml) and diisopropylether (100 ml)and dried. The solvent was evaporated under reduced pressure to give thetitled compound (4.1 g, 77%).

¹H-NMR (CDCl₃) δ: 4.78 (1H, s), 7.44 (1H, d, J=8.2 Hz), 7.59 (1H, s),8.24 (1H, d, J=8.2 Hz).

Example 85

2-(2-Pyridyl)-7-trifluoromethyl-4H-1,3-benzothiazine-4-one

A mixture of 4-trifluoromethylthiosalicylic acid (2.5 g, 11 mmol),2-cyanopyridine (1.2 g, 11 mmol) and pyridine (10 m) was refluxed for 10hrs. After cooling, the precipitated crystals were collected byfiltration and recrystallized from tetrahydrofuran-hexane to give thetitled compound (1.9 g, 54%).

mp. 175.8-177.0° C.

IR (KBr): 3049, 1678, 1660, 1574, 1537, 1334, 1305, 1172, 1084, 792cm⁻¹.

¹H-NMR (CDCl₃) δ: 7.57 (1H, m), 7.83-7.87 (2H, m), 7.94 (1H, m), 8.53(1H, dd, J=0.9, 7.9 Hz), 8.66 (1H, d, J=8.2 Hz), 8.76 (1H, m).

Elemental Analysis for C₁₄H₇N₂OSF₃

Calcd. C, 54.54; H, 2.29; N, 9.09.

Found C, 54.58; H, 2.14; N, 9.15.

Reference Example 18

6-[(4,4-Dimethoxybutyl)amino]nicotinenitrile

A mixture of 2-chloro-5-cyanopyridine (8.0 g, 57 mmol),4-aminobutylaldehyde dimethylacetal (19.2 g, 144 mmol) and ethanol (120ml) were refluxed for 15 hrs. The reaction mixture was concentrated,subjected to a column chromatography, eluted with hexane-ethyl acetate(1:1, v/v) and recrystallized from ethyl acetate-hexane to give thetitled compound (11.8 g, 87%)

mp. 74.0-76.0° C.

IR (KBr): 3358, 2949, 2216, 1606, 1518, 1371, 1130, 1070, 823 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.70-1.72 (4H, m), 3.33 (6H, s), 3.36 (2H, m), 4.39(1H, m), 5.21 (1H, br s), 6.36 (1H, d, J=8.8 Hz), 7.55 (1H, dd, J=2.2,8.8 Hz), 8.35 (1H, d, J=2.2 Hz)

Elemental Analysis for C₁₂H₁₇N₃O₂

Calcd. C, 61.26; H, 7.28; N, 17.86.

Found C, 61.29; H, 6.98; N, 17.82.

Example 86

2-[6-[(4,4-Dimethoxybutyl)amino]-3-pyridyl]-4H-1,3-benzothi azine-4-one

A mixture of 6-[(4,4-dimethoxybutyl)amino]nicotinenitrile (4.5 g, 19mmol), methyl thiosalicylate (6.5 g, 38 mmol), triethylamine (6.0 ml, 43mmol) and toluene (15 ml) was refluxed for 20 hrs. After cooling, theprecipitated crystals were collected and recrystallized fromtetrahydrofuran-hexane to give the titled compound (4.0 g, 56%).

mp. 157.2-158.5° C.

IR (KBr): 3290, 2947, 1604, 1504, 1454, 1248, 1128, 1099, 1066, 744cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.72-1.74 (4H, m), 3.34 (6H, s), 3.43 (2H, m), 4.41(1H, m), 5.37 (1H, br s), 6.45 (1H, d, J=9.0 Hz), 7.49 (1H, dd, J=1.3,7.7 Hz), 7.54-7.63 (2H, m), 8.28 (1H, dd, J=2.4, 9.0 Hz), 8.50 (1H, dd,J=1.7, 7.7 Hz), 8.93 (1H, d, J=2.4 Hz).

Elemental Analysis for C₁₉H₂₁N₃O₃S

Calcd. C, 61.44; H, 5.70; N, 11.31.

Found C, 61.41; H, 5.90; N, 11.44.

Example 87

tert-Butyl 3-[6-(6,8-dimethoxy-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propoxy]propanoate

A mixture of 3,5-dimethylthiosalicylate (1.1 g, 6.1 mmol), tert-butyl3-[3-(6-cyano-2-pyridyl)propoxy]propanoate (1.6 g, 5.5 mmol) andpyridine (10 ml) was stirred for 8 hrs. The reaction mixture wasconcentrated under reduced pressure. The residue was subjected to asilica gel column chromatography, eluted with hexane-ethyl acetate (2:1,v/v) and recrystallized from ethyl acetate-hexane to give the titledcompound (1.4 g, 51%)

mp. 105.3-107.3° C.

IR (KBr): 2974, 2930, 2868, 1730, 1659, 1537, 1454, 1365, 1323, 1159,1115 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 2.12 (2H, tt, J=6.4, 7.5 Hz), 2.46 (3H,s), 2.50 (2H, t, J=6.4 Hz), 2.55 (3H, s), 2.99 (2H, t, J=7.5 Hz), 3.57(2H, t, J=6.4 Hz), 3.70 (2H, t, J=6.4 Hz), 7.36 (1H, S), 7.38 (1H, d,J=7.5 Hz), 7.78 (1H, dd, J=7.5, 7.7 Hz), 8.26 (1H, s), 8.36 (1H, d,J=7.7 Hz).

Elemental Analysis for C₂₅H₃₀N₂O₄S

Calcd. C, 66.05; H, 6.65; N, 6.16.

Found C, 66.06; H, 6.85; N, 6.12.

Example 88

3-[6-(6,8-Dimethoxy-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propoxy]propanoic acid

A mixture of tert-butyl3-[6-(6,8-dimethoxy-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propoxy]propanoate (1.1 g, 2.4 mmol) and trifluoroacetic acid (5 ml)was stirred under ice cooling condition for 3 hrs. The reaction mixturewas concentrated. The residue was subjected to a silica gel columnchromatography, eluted with ethyl acetate-methanol (10:1, v/v) andrecrystallized from ethanol-hexane to give the titled compound (0.48 g,49%)

mp. 156.5-157.1° C.

IR (KBr): 2943, 2868, 1730, 1655, 1535, 1327, 1182, 1113, 993 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.11 (2H, tt, J=6.2, 7.5 Hz), 2.43 (3H, s), 2.51 (3H,s), 2.63 (2H, t, J=6.2 Hz), 2.95 (2H, t, J=7.5 Hz), 3.57 (2H, t, J=6.2Hz), 3.74 (2H, t, J=6.2 Hz), 7.33 (1H, s), 7.34 (1H, d, J=7.5 Hz), 7.76(1H, dd, J=7.5, 7.7 Hz), 8.22 (1H, s), 8.34 (1H, d, J=7.7 Hz)

Elemental Analysis for C₂₁H₂₂N₂O₄S·0.5H₂O

Calcd. C, 61.90; H, 5.69; N, 6.87.

Found C, 62.14; H, 5.48; N, 6.79.

Example 89

2-[2-(4-Methylthio)phenoxy-3-pyridyl]-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (0.86 g, 5.1 mmol),4-(4-methylthiophenoxy)benzonitrile (1.21 g, 5.0 mmol), triethylamine(1.00 ml, 7.2 mmol) and toluene (10 ml) was refluxed under nitrogenatmosphere for 16 hrs. The reaction mixture was concentrated, subjectedto a silica gel column chromatography, eluted with ethyl acetate-hexane(2:1, v/v) and recrystallized from ethyl acetate-hexane to give thetitled compound (0.21 g, 11%).

mp 140.5-140.6° C.

IR (KBr): 1661, 1599, 1584, 1522, 1476, 1439, 1372, 1279, 1238, 1204,1165, 1127, 1096, 1065, 1030, 1015, 924, 837, 745 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.50 (3H, s), 6.94-7.02 (1H, m), 7.11 (2H, d, J=8.6Hz), 7.33 (2H, d, J=8.6 Hz), 8.35-8.59 (2H, m), 8.93 (1H, d, J=2.5 Hz).

Elemental Analysis for C₂₀H₁₄N₂O₂S₂

Calcd. C, 63.47; H, 3.73; N, 7.40.

Found C, 63.20; H, 3.83; N, 7.43.

Example 90

2-[2-(4-Methyl)phenylthio-3-pyridyl]-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (1.50 g, 8.9 mmol),2-(4-methylphenylthio)-5-pyridinenitrile (2.00 g, 8.8 mmol),triethylamine (1.80 ml, 12.9 mmol) and toluene (10 ml) was refluxedunder nitrogen atmosphere for 10 hrs. The reaction mixture wasconcentrated. The residue was combined with water and extracted withethyl acetate. The extract was washed with water and dried. The solventwas evaporated. The residue was subjected to a silica gel columnchromatography, eluted with ethyl acetate-hexane (3:1, v/v) andrecrystallized from ethanol to give the titled compound (0.39 g, 12%).

mp 172.6-172.8° C.

IR (KBr): 1661, 1578, 1516, 1448, 1360, 1289, 1238, 1111, 1096, 920cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.40 (3H, s), 6.95 (1H, d, J=8.6 Hz), 7.25-7.74 (7H,m), 8.24 (1H, dt, J=2.0, 6.7 Hz), 8.51 (1H, d, J=7.6 Hz), 9.14 (1H, s).

Elemental Analysis for C₂₀H₁₄N₂OS₂

Calcd. C, 66.27; H, 3.89; N, 7.73.

Found C, 66.31; H, 3.86; N, 7.75.

Example 91

2-(6-Ethoxy-3-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (1.85 g, 11.0 mmol),2-ethoxy-5-cyanopyridine (1.48 g, 10.0 mmol), triethylamine (1.80 ml,12.9 mmol) and toluene (10 ml) was refluxed under nitrogen atmospherefor 18 hrs. The reaction mixture was concentrated. The residue wascombined with water and extracted with ethyl acetate. The extract waswashed with water and dried. The solvent was evaporated. The residue wassubjected to a silica gel column chromatography, eluted with ethylacetate-hexane (2:1, v/v) and recrystallized from chloroform-ethylacetate to give the titled compound (0.56 g, 20%).

mp. 152.3-156.2° C.

IR (KBr): 1661, 1601, 1572, 1526, 1497, 1439, 1399, 1383, 1348, 1285,1258, 1246, 1125, 1101, 1034, 930, 835, 747 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.42 (3H, t, J=7.1 Hz), 4.46 (2H, q, J=7.1 Hz), 6.83(1H, d, J=8.6 Hz), 7.47-7.74 (3H, m), 8.39 (1H, dd, J=2.6, 8.9 Hz), 8.52(1H, dd, J=1.7, 8.6 Hz), 8.96 (1H, d, J=2.6 Hz).

Elemental Analysis for C₁₅H₁₂N₂O₂S

Calcd. C, 63.36; H, 4.25; N, 9.85.

Found C, 63.28; H, 4.15; N, 9.93.

Example 92

2-[6-(Isobutylthio)-3-pyridyl]-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (1.01 g, 6.0 mmol),2-isobutylthio-5-cyanopyridine (1.03 g, 5.0 mmol), triethylamine (0.98ml, 7.0 mmol) and toluene (10 ml) was refluxed under nitrogen atmospherefor 20 hrs. The reaction mixture was concentrated. The residue wassubjected to a silica gel column chromatography, eluted with ethylacetate-hexane (2:1, v/v) and recrystallized from ethylacetate-isopropylether to give the titled compound (0.40 g, 23%).

mp. 92.8-93.1° C.

IR (KBr): 1661, 1582, 1578, 1541, 1514, 1458, 1358, 1289, 1240, 1113,1096, 1063, 1030, 922, 739 cm⁻¹.

¹H-NMR (CDCl₃) δ: 0.95 (3H, s), 0.97 (3H, s), 1.56-1.86 (3H, m), 3.24(2H, t, J=7.6 Hz), 7.27 (1H, d, J=9.4 Hz), 7.46-7.68 (3H, m), 8.26 (1H,dd, J=2.3, 8.6 Hz), 8.52 (1H, dd, J=1.4, 7.7 Hz), 9.16 (1H, d, 2.3 Hz).

Elemental Analysis for C₁₈H₁₈N₂OS₂

Calcd. C, 63.13; H, 5.30; N, 8.18.

Found C, 63.11; H, 5.13; N, 8.24.

Example 93

2-[6-Isopropoxy-3-pyridyl]-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (1.85 g, 11.0 mmol),2-isopropoxy-5-cyanopyridine (1.62 g, 10.0 mmol), triethylamine (1.80ml, 12.9 mmol) and toluene (10 ml) was refluxed under nitrogenatmosphere for 30 hrs. The reaction mixture was concentrated. Theresidue was subjected to a silica gel column chromatography, eluted withethyl acetate-hexane (2:1, v/v) and recrystallized from ethylacetate-isopropylether to give the titled compound (0.89 g, 30%).

mp. 109.7-110.4° C.

IR (KBr): 1663, 1595, 1570, 1522, 1487, 1381, 1285, 1238, 1096, 1063,1030, 947, 922, 837, 745 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.37 (3H, s), 1.39 (3H, s), 5.38-5.47 (1H, m), 6.78(1H, d), 7.43 (3H, m), 8.38 (1H, dd, J=2.5, 8.8 Hz), 8.52 (1H, d, J=7.6Hz), 8.96 (1H, d, J=2.5 Hz).

Elemental Analysis for C₁₆H₁₄N₂O₂S

Calcd. C, 64.41; H, 4.73; N, 9.39.

Found C, 64.26; H, 4.70; N, 9.26.

Example 94

2-[6-(2-Ethoxyethoxy)-3-pyridyl]-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (2.96 g, 17.6 mmol),5-cyano-2-(2-ethoxy)ethoxypyridine (3.07 g, 16.0 mmol), triethylamine(2.37 ml, 17.0 mmol) and toluene (15 ml) was refluxed under nitrogenatmosphere for 40 hrs. The reaction mixture was concentrated. Theresidue was subjected to a silica gel column chromatography, eluted withethyl acetate-hexane (1:1, v/v) and recrystallized from acetone-ethylacetate-isopropylether to give the titled compound (3.01 g, 57%).

mp. 93.6-94.9° C.

IR (KBr): 1661, 1597, 1522, 1487, 1391, 1287, 1238, 1125, 1098, 1046,914, 839, 745 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.24 (3H, t, J=7.1 Hz), 3.60 (2H, q, J=7.1 Hz),3.72-3.88 (2H, m), 4.50-4.64 (2H, m), 6.91 (1H, d, J=8.9 Hz), 7.42-7.69(3H, m), 8.39 (1H, dd, J=2.4, 8.9 Hz), 8.52 (1H, d, J=7.6 Hz), 8.96 (1H,s).

Elemental Analysis for C₁₇H₁₆N₂O₃S

Calcd. C, 62.18; H, 4.91; N, 8.53.

Found C, 62.22; H, 4.91; N, 8.56.

Example 95

2-[2-[[5-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]oxy]-1H-isoindole-1,3(2H)-dione

A mixture of methyl thiosalicylate (2.75 g, 16.4 mmol),5-cyano-2-(2-succinimido)ethoxypyridine (4.00 g, 13.6 mmol),triethylamine (2.51 ml, 18.0 mmol) and toluene (20 ml) was refluxedunder nitrogen atmosphere for 36 hrs. The reaction mixture was cooled,and the precipitated crystals (4.15 g) were collected by filtration andrecrystallized from chloroform-methanol to give the titled compound(3.64 g, 62%)

mp. 212.4-212.6° C.

IR (KBr): 1773, 1713, 1661, 1597, 1522, 1487, 1391, 1285, 1240, 1127,1098, 1019, 912, 839, 745 cm⁻¹.

¹H-NMR (CDCl₃) δ: 4.13 (2H, t, J=5.1 Hz), 4.70 (2H, t, J=5.1 Hz), 6.81(1H, d, J=8.8 Hz), 7.42-7.89 (11H, m), 8.36 (1H, d, J=2.5 Hz), 8.51 (1H,d, J=7.9 Hz), 8.88 (1H, s).

Elemental Analysis for C₂₃H₁₅N₃O₄S

Calcd. C, 64.33; H, 3.52; N, 9.78.

Found C, 63.19; H, 3.51; N, 9.65.

Example 96

Ethyl 6-{[5-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]oxy}hexano ate

A mixture of methyl thiosalicylate (0.71 g, 4.2 mmol), ethyl6-(5-cyanopyridin-2-yl)oxyhexanoate (1.00 g, 3.8 mmol), triethylamine(0.63 ml, 4.5 mmol) and toluene (12 ml) was refluxed under nitrogenatmosphere for 30 hrs. The reaction mixture was concentrated. Theresidue was subjected to a silica gel column chromatography, eluted withethyl acetate-hexane (2:1, v/v) and recrystallized from ethylacetate-isopropylether to give the titled compound (0.22 g, 14%)

mp. 73.6-73.9° C.

IR (KBr): 1730, 1665, 1597, 1572, 1524, 1489, 1439, 1396, 1370, 1287,1238, 1098, 1030, 922, 746 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.25 (3H, t, J=7.1 Hz), 1.37-1.88 (6H, m) 2.33 (2H, t,J=7.4 Hz), 4.13 (2H, q, J=7.1 Hz), 4.40 (2H, t, J=6.6 Hz), 6.83 (1H, d,8.8 Hz), 7.36-7.64 (3H, m), 8.40 (1H, dd, J=2.6, 8.8 Hz), 8.52 (1H, dd,J=1.7, 7.7 Hz), 8.96 (1H, d, J=2.6 Hz).

Elemental Analysis for C₂₁H₂₂N₂O₄S

Calcd. C, 63.30; H, 5.56; N, 7.03.

Found C, 63.21; H, 5.54; N, 7.10.

Example 97

Ethyl 2-{[5-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]thioxy}ace tate

A mixture of methyl thiosalicylate (0.84 g, 5.0 mmol), ethyl3-[2-(5-cyanopyridin-2-yl)thio]propionate (1.18 g, 5.0 mmol),triethylamine (0.84 ml, 6.0 mmol) and toluene (10 ml) was refluxed undernitrogen atmosphere for 15 hrs. The reaction mixture was diluted withethyl acetate, washed with water, dried and concentrated under reducedpressure. The residue was subjected to a silica gel columnchromatography, eluted with hexane-ethyl acetate (2:1, v/v) andrecrystallized from ethyl acetate-isopropylether to give the titledcompound (0.71 g, 38%).

mp. 115.7-116.0° C.

IR (KBr): 1730, 1661, 1582, 1541, 1516, 1460, 1358, 1291, 1240, 1113,1096, 1063, 1030, 922, 748, 739 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.27 (3H, t, J=7.1 Hz), 2.80 (2H, t, J=7.0 Hz), 3.50(2H, t, J=7.0 Hz), 4.18 (2H, q, J=7.1 Hz), 7.18-7.26 (1H, m), 7.44-7.65(3H, m), 8.27 (1H, dd, J=2.5, 8.6 Hz), 8.53 (1H, dd, J 1.5, 7.6 Hz),9.16 (1H, dd, J=0.6, 2.5 Hz).

Elemental Analysis for C₁₈H₁₆N₂O₃S₂

Calcd. C, 58.04; H, 4.33; N, 7.52.

Found C, 57.88; H, 4.04; N, 7.44.

Example 98

tert-Butyl 3-{3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-3-pyridyl]propoxy}propanoate

A mixture of methyl thiosalicylate (2.80 g, 16.6 mmol), a mixture oftert-butyl 3-[(2-cyanopyridin-3-yl)propoxy]propionate and tert-butyl3-[(2-cyanopyridin-5-yl)propoxy]propionate (ca. 9:1, 4.55 g, 15.7 mmol),triethylamine (2.02 g, 20 mmol) and toluene (20 ml) was refluxed undernitrogen atmosphere for 20 hrs. The reaction mixture was concentratedunder reduced pressure. The residue was subjected to a silica gel columnchromatography, eluted with ethyl acetate-hexane (2:1, v/v) to give thetitled compound (1.10 g, 16%).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 1.85-1.98 (2H, m), 2.49 (2H, t, J=6.3Hz), 2.81 (2H, t, J=7.6 Hz), 3.47 (2H, t, J=6.0 Hz), 3.67 (2H, t, J=6.3Hz), 7.45-7.72 (4H, m), 8.46 (1H, d, J=8.0 Hz), 8.54 (1H, d, J=8.0 Hz),8.56 (1H, s)

Example 99

3-{3-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-3-pyridyl]propoxy} propionicacid

tert-Butyl 3-{3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-3-pyridyl]propoxy}propanoate (1.0 g, 2.3 mmol) and trifluoroacetic acid (4.0 ml) wasstirred under ice cooling condition for 5 hrs. The reaction mixture wasconcentrated under reduced pressure, diluted with chloroform, washedwith water and dried. The solvent was evaporated. The residue wassubjected to a silica gel column chromatography, eluted with ethylacetate-methanol (20:1, v/v) and recrystallized from chloroform-ethylacetate to give the titled compound (0.55 g, 66%)

mp. 145.2-146.6° C.

IR (KBr): 3007, 2924, 2884, 1725, 1638, 1566, 1526, 1431, 1316, 1287,1248, 1202, 1113, 1065, 1030, 945, 860, 748 cm⁻¹.

¹H-NMR (DMSO-d₆) δ: 1.84 (2H, t, J=6.9 Hz), 2.44 (2H, t, J=6.2 Hz), 2.75(2H, t, 7.5 Hz), 3.38 (2H, t, J=6.1 Hz), 3.57 (2H, t, J=6.2 Hz),7.58-7.91 (4H, m), 8.25 (1H, d, J=8.1 Hz), 8.33 (1H, d, J=7.9 Hz), 8.63(1H, s), 12.13 (1H, s)

Elemental Analysis for C₁₉H₁₈N₂O₄S·0.5H₂O

Calcd. C, 60.14; H, 5.05; N, 7.38.

Found C, 60.37; H, 4.95; N, 7.27.

Reference Example 19

3-[(6-Cyano-2-pyridyl)oxy]-N,N-dimethylaminomethylene-2,2-dimethyl-1-propanesulfonamide

Sodium hydride (60% oil, 0.26 g, 6.5 mmol) was suspended intetrahydrofuran (10 ml), and to the mixture, a solution of2,2-dimethyl-3-hydroxy-1-propane-N,N-dimethylaminomethylene sulfonamideproduced in accordance with M. Kuwahara et al.'s method (Chemical andPharmaceutical Bulletin, Vol. 44, pp. 122-131, 1996) (1.34 g, 6.0 mmol)in tetrahydrofuran (15 ml) was added dropwise with stirring under icecooling condition. The reaction mixture was stirred at the sametemperature for 10 minutes. 2-Chloro-6-cyanopyridine (0.69 g, 5.0 mmol)was added to the reaction mixture. The reaction mixture was refluxed for3 hrs, poured into ice water and extracted with ethyl acetate. Theextract was washed with water and dried. The solvent was evaporatedunder reduced pressure. The residue was ground by isopropylether andcollected by filtration to give the titled compound (1.60 g, 99%).

IR (KBr): 2236, 1628, 1447, 1335, 1271, 1208, 1117, 1022, 910, 860, 847,810 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.28 (6H, s), 2.99 (3H, s), 3.10 (3H, s), 3.19 (2H,s), 4.23 (2H, s), 6.98 (1H, d, J=8.4 Hz), 7.29 (1H, dd, J=0.6, 7.2 Hz),7.66 (1H, dd, J=7.4, 8.5 Hz), 8.02 (1H, s)

Example 100

N,N-(Dimethylaminomethylene)-2,2-dimethyl-3-{[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]oxy}-1-propanesulfonamide

A mixture of methyl thiosalicylate (0.87 g, 5.2 mmol),3-[(6-cyano-2-pyridyl)oxy]-N,N-dimethylaminomethylene-2,2-dimethyl-1-propanesulfonamide (1.32 g, 4.1 mmol), triethylamine (0.61 g,6.0 mmol) and toluene (15 ml) was refluxed with stirring for 20 hrs. Thereaction mixture was concentrated under reduced pressure. The residuewas subjected to a silica gel column chromatography, eluted with ethylacetate-methanol (20:1, v/v) and recrystallized from ethyl acetate togive the titled compound (0.90 g, 48%).

mp. 174.5-175.3° C.

IR (KBr): 1651, 1638, 1574, 1537, 1454, 1337, 1271, 1240, 1123, 1040,988, 910, 858, 847, 812, 729 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.36 (6H, s), 2.89 (3H, s), 3.03 (3H, s), 3.27 (2H,s), 4.39 (2H, s), 6.99 (1H, dd, J=0.6, 8.3 Hz), 7.59-7.65 (3H, m), 7.76(1H, dd, J=7.5, 8.2 Hz), 8.02 (1H, s), 8.13 (1H, dd, J=0.6, 7.5 Hz),8.54 (1H, dd, J=1.4, 9.0 Hz).

Elemental Analysis for C₂₁H₂₄N₄O₄S₂

Calcd. C, 54.76; H, 5.25; N, 12.16.

Found C, 54.44; H, 5.22; N, 12.12.

Reference Example 20

tert-Butyl 3-[3-(4-pyridyl)propoxy]propanoate

Triton B (40% methanol solution, 0.5 ml) was concentrated under reducedpressure, and 4-pyridinepropanol (10.2 g, 74.5 mmol) was added thereto.After 15 minutes, tert-butyl acrylate (9.59 g, 74.8 mmol) was added tothe mixture, and the mixture was stirred at room temperature for 6 hrs.The reaction mixture was subjected to a silica gel columnchromatography, eluted with hexane-ethyl acetate (1:1, v/v) to give thetitled compound (17.1 g, 86%).

IR (KBr): 2978, 2868, 1730, 1603, 1556, 1159, 1113, 991 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 1.85-1.91 (2H, m), 2.49 (2H, t, J=6.3Hz), 2.68 (2H, t, J=7.4 Hz), 3.44 (2H, t, J=6.2 Hz), 3.66 (2H, t, J=6.4Hz), 7.12 (2H, d, J=5.7 Hz), 8.49 (2H, d, J=5.7 Hz).

Reference Example 21

tert-Butyl 3-[3-(4-pyridyl)propoxy]propanoate N-oxide

tert-Butyl 3-[3-(4-pyridyl)propoxy]propanoate (16.5 g, 62.2 mmol) wasdissolved in ethyl acetate (50 ml). 3-Chloroperbenzoic acid (ca. 77%,14.6 g, 65.2 mmol) was added to the mixture at room temperature. Thereaction mixture was stirred for 23 hrs, subjected to a silica gelcolumn chromatography and eluted with hexane-ethyl acetate (2:1, v/v) togive the titled compound (16.9 g, 96%) as an oil.

IR (KBr): 3584, 2934, 1732, 1714, 1487, 1454, 1234, 1157 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 1.85-1.91 (2H, m), 2.48 (2H, t, J=6.2Hz), 2.71 (2H, t, J=7.4 Hz), 3.44 (2H, t, J=5.6 Hz), 3.66 (2H, t, J=6.2Hz), 7.15 (2H, d, J=6.8 Hz), 8.14 (2H, d, J=6.8 Hz).

Reference Example 22

tert-Butyl 3-[3-[2-cyano-4-pyridyl]propoxy]propanoate

tert-Butyl 3-[3-(4-pyridyl)propoxy]propanoate N-oxide (16.0 g, 56.9mmol) and trimethylsilyl anilide (12.4 g, 125.1 mmol) were dissolved innitroethane (50 ml).

N,N-Dimethylcarbamoyl chloride (12.8 g, 119.4 mmol) was added dropwiseto the mixture. The reaction mixture was stirred at room temperature for18 hrs and combined with saturated aqueous sodium hydrogen carbonatesolution. The organic layer was separated, dried and concentrated. Theresidue was subjected to a silica gel column chromatography, eluted withhexane-ethyl acetate (2:1, v/v) to give the titled compound (16.2 g,98%) as an oil.

IR (KBr): 2235, 1730, 1597, 1554, 1367, 1159, 1114 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 1.87-1.96 (2H, m), 2.49 (2H, t, J=6.3Hz), 2.79 (2H, t, J=7.3 Hz), 3.46 (2H, t, J=6.0 Hz), 3.67 (2H, t, J=6.3Hz), 7.40 (1H, d, J=5.0 Hz), 7.58 (1H, s), 8.59 (1H, d, J=5.0 Hz).

Example 101

tert-Butyl3-[3-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propoxy]propanoate

A mixture of methyl thiosalicylate (7.4 g, 43.8 mmol), tert-butyl3-[3-[2-cyano-4-pyridyl]propoxy]propanoate (14.0 g, 48.2 mmol),triehthylamine (7.1 g, 70.2 mmol) and toluene (37 ml) was refluxed undernitrogen atmosphere for 24 hrs. The reaction mixture was concentratedunder reduced pressure, subjected to a column chromatography and elutedwith ethyl acetate-hexane (3:2, v/v) to give the titled compound (17.7g, 86%).

mp. 81.1-82.2° C.

IR (KBr): 1728, 1664, 1572, 1537, 1366, 1281, 1159, 1115, 1096 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 1.92-1.97 (2H, m), 2.50 (2H, t, J=6.4Hz), 2.82 (2H, t, J=7.5 Hz), 3.46 (2H, t, J=6.1 Hz), 3.67 (2H, t, J=6.4Hz), 7.39 (1H, m), 7.60-7.69 (3H, m), 8.42 (1H, s), 8.56 (1H, d, J=6.7Hz), 8.62 (1H, d, J=4.9 Hz).

Elemental Analysis for C₂₃H₂₆N₂O₄S

Calcd. C, 64.77; H, 6.14; N, 6.57.

Found C, 64.70; H, 6.03; N, 6.44.

Example 102

3-[3-[2-(4-Oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propoxy] propanoicacid

A mixture of tert-butyl3-[3-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propoxy] propanoate(3.9 g, 9.1 mmol) and trifluoroacetic acid (30 ml) was stirred at roomtemperature for 1.5 hrs. The reaction mixture was concentrated underreduced pressure to obtain crystals which were collected by filtrationand recrystallized from chloroform to give the titled compound (3.0 g,89%).

mp. 153.8-153.9° C.

IR (KBr): 1732, 1714, 1661, 1570, 1537, 1470, 1441, 1283, 1100 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.94 (2H, m), 2.65 (2H, t, J=5.7 Hz), 2.88 (2H, t,J=6.6 Hz), 3.39 (2H, t, J=5.8 Hz), 3.76 (2H, t, J=5.5 Hz), 7.36 (1H, m),7.63-7.72 (3H, m), 8.39 (1H, s), 8.56-8.62 (2H, m).

Elemental Analysis for C₁₉H₁₈N₂O₄S

Calcd. C, 61.61; H, 4.90; N, 7.56.

Found C, 61.31; H, 4.79; N, 7.45.

Example 103

N-Butyl-N-methyl-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridinecarboxamide

A mixture of N-butyl-N-methyl-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridinecarboxylic acid (0.45 g, 1.6 mmol), N-methylbutylamine (0.31 g, 3.5mmol), WSC (0.63 g, 3.2 mmol), HOBt (0.44 g, 3.2 mmol) and DMF (10 ml)was stirred at 80° C. for 15 hrs. The reaction mixture was diluted andextracted with ethyl acetate. The extract was washed with water anddried. The solvent was evaporated. The residue was subjected to a silicagel column chromatography, eluted with ethyl acetate-hexane (3:2, v/v)and recrystallized from ethyl acetate-hexane to give the titled compound(0.42 g, 75%).

mp. 80.0-81.6° C.

IR (KBr): 2955, 1666, 1633, 1572, 1537, 1439, 1300, 1095, 748 cm⁻¹.

¹H-NMR (CDCl₃) δ: 0.85 (1.5H, t, J=7.3 Hz), 1.02 (1.5H, t, J=7.3 Hz),1.23 (1H, m), 1.47 (1H, m), 1.71-1.80 (2H, m), 3.18 (1.5H, s), 3.23(1.5H, s), 3.46 (1H, m), 3.63 (1H, m), 7.61-7.70 (3H, m), 7.87-8.04 (2H,m), 8.55-8.60 (2H, m)

Elemental Analysis for C₁₉H₁₉N₃O₂S 0.75H₂O

Calcd. C, 62.19; H, 5.63; N, 11.45.

Found C, 62.37; H, 5.38; N, 11.70.

Example 104

2-[6-(1-Pyrrolidinylcarbonyl)-4H-1,3-benzothiazine-4-one

A mixture of N-butyl-N-methyl-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridinecarboxylic acid (0.45 g, 1.6 mmol), pyrrolidine (0.30 g, 4.1 mmol),WSC (0.62 g, 3.2 mmol), HOBt (0.43 g, 3.1 mmol) and DMF (10 ml) wasstirred at 80° C. for 15 hrs. After cooling, the precipitates werecollected by filtration, subjected to a silica gel columnchromatography, eluted with ethyl acetate-methanol (3:1, v/v) andrecrystallized from chlorobenzene-hexane to give the titled compound(0.28 g, 51%).

mp. 232.0-234.0° C.

IR (KBr): 3493, 2970, 1660, 1622, 1572, 1537, 1421, 1302, 1097, 758cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.95-2.09 (4H, m), 3.77 (2H, t, J=6.5 Hz), 4.03 (2H,t, J=6.5 Hz), 7.61-7.73 (3H, m), 8.03 (1H, m), 8.21 (1H, m), 8.54-8.61(2H, m).

Elemental Analysis for C₁₈H₁₅N₃O₂S

Calcd. C, 64.08; H, 4.48; N, 12.45.

Found C, 64.03; H, 4.38; N, 12.39.

Example 105

N,N-Diethyl-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridineca rboxamide

A mixture of N-butyl-N-methyl-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridinecarboxylic acid (0.45 g, 1.6 mmol), diethylamine (0.50 g, 6.8 mmol),WSC (0.62 g, 3.2 mmol), HOBt (0.43 g, 3.1 mmol) and DMF (10 ml) wasstirred at 80° C. for 15 hrs. The reaction mixture was diluted withwater and extracted with ethyl acetate. The extract was washed withwater and dried. The solvent was evaporated. The residue was subjectedto a silica gel column chromatography, eluted with ethyl acetate-hexane(2:1, v/v) and recrystallized from tetrahydrofuran-hexane to give thetitled compound (0.37 g, 69%)

mp. 194.0-194.3° C.

IR (KBr): 2970, 1664, 1633, 1572, 1537, 1439, 1300, 1236, 1097, 742cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.33 (3H, t, J=7.1 Hz), 1.33 (3H, t, J=7.0 Hz), 3.51(2H, q, J=7.0 Hz), 3.64 (2H, q, J=7.1 Hz), 7.62-7.70 (3H, m), 7.89 (1H,dd, J=1.1, 7.7 Hz), 8.01 (1H, m), 8.54-8.59 (2H, m).

Elemental Analysis for C₁₈H₁₇N₃O₂S

Calcd. C, 63.70; H, 5.05; N, 12.38.

Found C, 63.70; H, 4.93; N, 12.40.

Example 106

tert-Butyl [[[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]carbonyl]amino]hexylcarbamate

A mixture of N-butyl-N-methyl-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridinecarboxylic acid (0.68 g, 2.3 mmol), tert-butylN-(6-aminohexyl)carbamate (0.83 g, 3.8 mmol), WSC (0.92 g, 4.8 mmol),HOBt (0.65 g, 4.8 mmol) and DMF (15 ml) was stirred at 80° C. for 24hrs. The reaction mixture was diluted with water and extracted withethyl acetate. The extract was washed with water and dried. The solventwas evaporated. The residue was subjected to a silica gel columnchromatography, eluted with ethyl acetate-hexane (3:1, v/v) andrecrystallized from tetrahydrofuran-hexane to give the titled compound(0.70 g, 60%).

mp. 145.1-145.4° C.

IR (KBr): 3350, 2932, 2858, 1693, 1680, 1666, 1572, 1537, 1440, 1302,1248, 1170, 1097, 746, 733 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.43 (9H, s), 1.43-1.56 (6H, m), 1.74 (2H, m), 3.14(2H, m), 3.57 (2H, m), 4.55 (1H, br s), 7.65-7.73 (3H, m), 7.93 (1H, m),8.08 (1H, m), 8.44 (1H, m), 8.57 (1H, m), 8.65 (1H, dd, J=0.6, 7.8 Hz).

Elemental Analysis for C₂₅H₃₀N₄O₄S

Calcd. C, 62.22; H, 6.27; N, 11.61.

Found C, 62.23; H, 6.39; N, 11.74.

Example 107

N-(6-Aminohexyl)-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridinecarboxamide hydrochloride

tert-Butyl [[[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]carbonyl]amino]hexylcarbamate (0.30 g, 0.62 mmol) was dissolved in ethyl acetate(15 ml), and a solution of 4 N hydrochloric acid in ethyl acetate (2.0ml, 8.0 mmol) was added thereto under ice cooling condition. Thereaction mixture was stirred at the same temperaturefor3 hrs.Theprecipitatedcrystalswerecollected by filtration and recrystallizedfrom methanol-diethyl ether to give the titled compound (0.15 g, 56%)

mp. 95.2-97.6° C.

IR (KBr): 3072, 2964, 1662, 1570, 1529, 1439, 1298, 1238, 1095, 748cm⁻¹.

¹H-NMR (DMSO-d₆) δ: 1.37-1.39 (4H, m), 1.60-1.63 (4H, m), 2.77 (2H, m),3.41 (2H, m), 7.75 (1H, m), 7.84-7.92 (2H, m), 7.97 (3H, br s),8.25-8.32 (2H, m), 8.39 (1H, d, J=8.1 Hz), 8.51 (1H, dd, J=2.3, 6.5 Hz),8.63 (1H, t, J=6.0 Hz)

Elemental Analysis for C₂₀H₂₃N₄O₂SCl·H₂O

Calcd. C, 54.97; H, 5.77; N, 12.82.

Found C, 55.10; H, 6.19; N, 12.99.

Reference Example 23

tert-Butyl methyl(2-pyridyl)carbamate N-oxide

A mixture of tert-butyl methyl (2-pyridyl)carbamate (14.4 g, 69 mmol),3-chloroperbenzoic acid (ca. 77%, 20.0 g, 89 mmol) and ethyl acetate(200 ml) was stirred at room temperature for 48 hrs. The reactionmixture was concentrated under reduced pressure, subjected to a silicagel column chromatography and eluted with ethyl acetate-methanol (10:1,v/v) to give the titled compound (14.1 g, 91%)

¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 3.18 (3H, s), 7.14-7.30 (3H, m) 8.24(1H, m).

Reference Example 24

tert-Butyl 6-cyano-2-pyridylmethylcarbamate

A mixture of tert-butyl methyl(2-pyridyl)carbamate N-oxide (14.1 g, 63mmol), trimethylsilyl cyanide (12.5 g, 126 mmol), N,N-dimethylcarbamoylchloride (13.5 g, 125 mmol) and nitroethane (120 ml) was stirred at roomtemperature for 48 hrs. The reaction mixture was concentrated underreduced pressure. The residue was subjected to a silica gel columnchromatography, eluted with hexane-ethyl acetate (10:1, v/v) andrecrystallized from ethyl acetate-hexane to give the titled compound(11.3 g, 77%).

mp. 96.4-96.6° C.

IR (KBr): 2980, 2231, 1709, 1591, 1346, 1294, 1161, 808 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.54 (9H, s), 3.42 (3H, s), 7.36 (1H, d, J=7.2 Hz),7.70 (1H, dd, J=7.2, 8.7 Hz), 8.11 (1H, d, J=8.7 Hz).

Elemental Analysis for C₁₂H₁₅N₃O₂

Calcd. C, 61.79; H, 6.48; N, 18.01.

Found C, 61.81; H, 6.29; N, 18.12.

Example 108

tert-Butyl methyl[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]carbamate

A mixture of methyl thiosalicylate (3.8 g, 22 mmol), tert-butyl6-cyano-2-pyridylmethylcarbamate (3.5 g, 15 mmol), triethylamine (4.0ml, 28 mmol) and toluene (10 ml) was refluxed for 14 hrs. After cooling,the precipitated crystals were collected by filtration andrecrystallized from tetrahydrofuran-hexane to give the titled compound(4.6 g, 82%).

mp. 195.6-196.3° C.

IR (KBr): 2972, 1703, 1651, 1574, 1537, 1344, 1153, 731 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.57 (9H, s), 3.57 (3H, s), 7.58-7.68 (3H, m), 7.81(1H, m), 8.10 (1H, d, J=8.4 Hz), 8.21 (1H, d, J=7.5 Hz), 8.55 (1H, m).

Elemental Analysis for C₁₉H₁₉N₃O₃S

Calcd. C, 61.77; H, 5.18; N, 11.37.

Found C, 61.88; H, 5.00; N, 11.53.

Example 109

2-(6-Methylamino-2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of tert-butyl methyl[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]carbama te (0.60 g, 1.6mmol) and trifluoroacetic acid (8 ml) was stirred at room temperaturefor 1 hr. The reaction mixture was concentrated under reduced pressureto give crystals, which were recrystallized from methanol-diethyl etherto give the titled compound (0.33 g, 74%).

mp. 206.9-208.0° C.

IR (KBr): 3341, 1651, 1614, 1574, 1537, 1531, 1298, 1242, 978, 738 cm⁻¹.

¹H-NMR (DMSO-d₆) δ: 2.93 (3H, d, J=4.3 Hz), 6.79 (1H, m), 7.06 (1H, d,J=4.3 Hz), 7.51 (1H, m), 7.62 (1H, m), 7.71 (1H, m), 7.81 (1H, m), 7.88(1H, m), 8.34 (1H, dd, J=1.0, 7.8 Hz)

Elemental Analysis for C₁₄H₁₁N₃OS

Calcd. C, 62.43; H, 4.12; N, 15.60.

Found C, 62.42; H, 3.99; N, 15.66.

Example 110

N-Methyl-N-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]ac etamide

A mixture of 2-(6-methylamino-2-pyridyl)-4H-1,3-benzothiazine-4-one(0.20 g, 0.74 mmol), acetyl chloride (0.18 g, 2.22 mmol) andN,N-dimethylacetamide (10 ml) was stirred at 80° C. for 1 hr. Aftercooling, the reaction mixture was poured into water and extracted withethyl acetate. The extract was washed with saturated brine and dried.The solvent was evaporated. The residue was recrystallized fromtetrahydrofuran-hexane to give the titled compound (0.20 g, 86%)

mp. 218.3-220.3° C.

IR (KBr): 3543, 3071, 1666, 1587, 1574, 1537, 1456, 1440, 1377, 1317,1284, 1236, 1097, 993, 734 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.33 (3H, s), 3.56 (3H, s), 7.60-7.76 (4H, m) 7.93(1H, m), 8.36 (1H, d, J=7.7 Hz), 8.55 (1H, m).

Elemental Analysis for C₁₆H₁₃N₃O₂S

Calcd. C, 61.72; H, 4.21; N, 13.50.

Found C, 61.64; H, 3.92; N, 13.42.

Example 111

N-Methyl-N-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]-2-thiophenecarboxamide

A mixture of 2-(6-methylamino-2-pyridyl)-4H-1,3-benzothiazine-4-one(0.20 g, 0.74 mmol), 2-thiophenecarbonyl chloride (0.28 g, 1.9 mmol) andN,N-dimethylacetamide (10 ml) was stirred at 80° C. for 2 hrs. Aftercooling, the reaction mixture was poured into water and extracted withethyl acetate. The extract was washed successively with saturatedaqueous sodium hydrogen carbonate solution and brine and dried. Thesolvent was evaporated. The residue was recrystallized fromtetrahydrofuran-hexane to give the titled compound (0.23 g, 83%)

mp. 191.5-192.9° C.

IR (KBr): 3067, 1643, 1572, 1523, 1450, 1442, 1360, 1313, 738 cm⁻¹.

¹H-NMR (CDCl₃) δ: 3.72 (3H, s), 6.90 (1H, m), 7.06 (1H, dd, J=1.1, 3.7Hz), 7.40-7.43 (2H, m), 7.61-7.70 (3H, m), 7.80 (1H, m), 8.35 (1H, d,J=7.6 Hz), 8.55 (1H, d, J=7.6 Hz).

Elemental Analysis for C₁₉H₁₃N₃O₂S₂

Calcd. C, 60.14; H, 3.45; N, 11.07.

Found C, 60.09; H, 3.34; N, 11.05.

Example 112

N-Methyl-N-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]-2-furamide

A mixture of 2-(6-methylamino-2-pyridyl)-4H-1,3-benzothiazine-4-one(0.20 g, 0.74 mmol), 2-furoyl chloride (0.26 g, 2.0 mmol) andN,N-dimethylacetamide (10 ml) was stirred at 80° C. for 2 hrs. Aftercooling, the reaction mixture was poured into water and extracted withethyl acetate. The extract was washed successively with saturatedaqueous sodium hydrogen carbonate solution and brine and dried. Thesolvent was evaporated. The residue was subjected to a silica gel columnchromatography and eluted with hexane-ethyl acetate (1:1, v/v). Theobtained crystals were recrystallized from ethyl acetate-hexane to givethe titled compound (0.21 g, 63%)

mp. 186.2-187.2° C.

IR (KBr): 3499, 1658, 1572, 1537, 1452, 1344, 1282, 1097, 746 cm⁻¹.

¹H-NMR (CDCl₃) δ: 3.71 (3H, s), 6.42 (1H, dd, J=1.7, 3.5 Hz), 6.95 (1H,m), 7.29 (1H, m), 7.39 (1H, d, J=7.7 Hz), 7.57-7.71 (3H, m), 7.84 (1H,m), 8.35 (1H, d, J=7.3 Hz), 8.55 (1H, dd, J=1.5, 7.7 Hz).

Elemental Analysis for C₁₉H₁₃N₃O₃S

Calcd. C, 62.80; H, 3.61; N, 11.56.

Found C, 62.76; H, 3.53; N, 11.61.

Example 113

N-Methyl-N-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]be nzamide

A mixture of 2-(6-methylamino-2-pyridyl)-4H-1,3-benzothiazine-4-one(0.20 g, 0.74 mmol), benzoyl chloride (0.44 g, 3.1 mmol) andN,N-dimethylacetamide (10 ml) was stirred at 80° C. for 20 hrs. Aftercooling, the reaction mixture was poured into water and extracted withethyl acetate. The extract was successively washed with saturatedaqueous sodium hydrogen carbonate solution and brine and dried. Thesolvent was evaporated. The residue was subjected to a silica gel columnchromatography and eluted with hexane-ethyl acetate (1:1, v/v). Theobtained crystals were recrystallized from ethyl acetate-hexane to givethe titled compound (0.13 g, 38%).

mp. 234.0-235.4° C.

IR (KBr): 3069, 1655, 1572, 1535, 1452, 1340, 1097, 729 cm⁻¹.

¹H-NMR (CDCl₃) δ: 3.71 (3H, s), 7.24-7.45 (6H, m), 7.61-7.72 (4H, m),8.25 (1H, d, J=7.6 Hz), 8.54 (1H, m).

Elemental Analysis for C₂₁H₁₅N₃O₂S

Calcd. C, 67.54; H, 4.05; N, 11.25.

Found C, 67.59; H, 4.05; N, 11.28.

Example 114

N-Methyl-N-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]pr opanamide

A mixture of 2-(6-methylamino-2-pyridyl)-4H-1,3-benzothiazine-4-one(0.25 g, 0.92 mmol), propionyl chloride (0.29 g, 3.1 mmol) andN,N-dimethylacetamide (10 ml) was stirred at 80° C. for 2 hrs. Aftercooling, the reaction mixture was poured into water and extracted withethyl acetate. The extract was successively washed with saturatedaqueous sodium hydrogen carbonate solution and brine and dried. Thesolvent was evaporated. The residue was recrystallized fromtetrahydrofuran-hexane to give the titled compound (0.15 g, 49%).

mp. 200.6-201.2° C.

IR (KBr): 3479, 3069, 2978, 2937, 1672, 1574, 1541, 1456, 1373, 1311,1284, 1236, 1095, 810, 731 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.21 (3H, t, J=7.3 Hz), 2.58 (2H, q, J=7.3 Hz), 3.55(3H, s), 7.60-7.72 (3H, m), 7.79 (1H, d, J=8.0 Hz), 7.92 (1H, m), 8.35(1H, d, J=7.6 Hz), 8.55 (1H, m).

Elemental Analysis for C₁₇H₁₅N₃O₂S

Calcd. C, 62.75; H, 4.65; N, 12.91.

Found C, 62.36; H, 4.44; N, 12.75.

Example 115

N-methyl-N-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]cyclohexanecarboxamide

A mixture of 2-(6-methylamino-2-pyridyl)-4H-1,3-benzothiazine-4-one(0.20 g, 0.72 mmol), cyclohexanecarbonyl chloride (0.22 g, 1.5 mmol) andN,N-dimethylacetamide (10 ml) was stirred at 80° C. for 2 hrs. Aftercooling, the reaction mixture was poured into water and extracted withethyl acetate. The extract was successively washed with saturatedaqueous sodium hydrogen carbonate solution and brine and dried. Thesolvent was evaporated. The residue was subjected to a silica gel columnchromatography and eluted with hexane-ethyl acetate (1:1, v/v). Theobtained crystals were recrystallized from tetrahydrofuran-hexane togive the titled compound (0.20 g, 71%).

mp. 184.4-185.8° C.

IR (KBr): 2932, 2854, 1666, 1572, 1537, 1452, 1284, 1238, 1095, 989,744, 733 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.15-1.31 (3H, m), 1.56-1.68 (3H, m), 1.79 (2H, m),1.90 (2H, m), 2.66 (1H, m), 3.52 (3H, s), 7.59-7.72 (4H, m), 7.94 (1H,m), 8.39 (1H, d, J=7.6 Hz), 8.56 (1H, m).

Elemental Analysis for C₂₁H₂₁N₃O₂S

Calcd. C, 66.47; H, 5.58; N, 11.07.

Found C, 66.48; H, 5.36; N, 11.24.

Example 116

6-Butoxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.35 g,1.3 mmol), 1-bromobutane (0.38 g, 2.7 mmol) and potassium carbonate(0.56 g, 4.0 mmol) and DMF (10 ml) was stirred at room temperature for15 hrs. The reaction mixture was diluted with water and extracted withethyl acetate. The extract was washed with water and dried. The solventwas evaporated. The obtained crystals were recrystallized fromtetrahydrofuran-hexane to give the titled compound (0.35 g, 83%).

mp. 160.9-161.8° C.

IR (KBr): 3053, 2951, 1660, 1643, 1599, 1537, 1469, 1344, 1282, 1234,1057, 794 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.00 (3H, t, J=7.3 Hz), 1.52 (2H, m), 1.82 (2H, m),4.12 (2H, t, J=6.5 Hz), 7.29 (1H, dd, J=2.8, 8.7 Hz), 7.51-7.55 (2H, m),7.90 (1H, m), 8.00 (1H, d, J=2.8 Hz), 8.55 (1H, d, J=7.9 Hz), 8.73 (1H,m)

Elemental Analysis for C₁₇H₁₆N₂O₂S

Calcd. C, 65.36; H, 5.16; N, 8.97.

Found C, 65.30; H, 4.95; N, 8.85.

Example 117

6-Isobutoxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.35 g,1.3 mmol), isobutyl bromide (0.64 g, 4.6 mmol) and potassium carbonate(0.57 g, 4.1 mmol) and DMF (10 ml) was stirred at room temperature for15 hrs. The reaction mixture was diluted with water and extracted withethyl acetate. The extract was washed with water and dried. The solventwas evaporated. The residue was subjected to a silica gel columnchromatography and eluted with hexane-ethyl acetate (2:1, v/v). Theobtained crystals were recrystallized from ethyl acetate-hexane to givethe titled compound (0.08 g, 19%).

mp. 135.5-136.5° C.

IR (KBr): 2959, 1659, 1601, 1531, 1464, 1344, 1278, 1236, 1055, 792cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.06 (6H, d, J=6.7 Hz), 2.14 (2H, m), 3.88 (2H, d,J=6.7 Hz), 7.31 (1H, dd, J=2.8, 8.8 Hz), 7.52-7.55 (2H, m), 7.91 (1H,m), 8.00 (1H, d, J=2.8 Hz), 8.55 (1H, m), 8.72 (1H, m).

Elemental Analysis for C₁₇H₁₆N₂O₂S

Calcd. C, 65.36; H, 5.16; N, 8.97.

Found C, 65.35; H, 5.08; N, 9.02.

Example 118

6-(3-Hydroxypropoxy)-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.40 g,1.5 mmol), 3-bromo-1-propanol (0.66 g, 4.7 mmol) and potassium carbonate(0.43 g, 3.1 mmol) and DMF (10 ml) was stirred at room temperature for15 hrs. The reaction mixture was diluted with water and extracted with amixture solvent of ethyl acetate and ethanol. The extract was washedwith water and dried. The solvent was evaporated. The obtained crystalswere recrystallized from ethanol-hexane to give the titled compound(0.27 g, 54%).

mp. 196.6-197.7° C.

IR (KBr): 3370, 2951, 1628, 1599, 1518, 1467, 1354, 1282, 1236, 1064,798 cm⁻¹.

¹H-NMR (DMSO-d₆) δ: 1.92 (2H, m), 3.60 (2H, m), 4.19 (2H, t, J=6.6 Hz),4.60 (1H, t, J=4.9 Hz), 7.45 (1H, m), 7.72-7.85 (3H, m), 8.10 (1H, m),8.34 (1H, d, J=7.7 Hz), 8.79 81H, d, J=3.6 Hz).

Elemental Analysis for C₁₆H₁₄N₂O₃S 0.25H₂O

Calcd. C, 60.27; H, 4.58; N, 8.79.

Found C, 60.34; H, 4.54; N, 8.67.

Example 119

6-(6-Hydroxyhexyloxy)-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.35 g,1.3 mmol), 6-bromohexanol (1.28 g, 7.0 mmol) and potassium carbonate(0.38 g, 2.7 mmol) and DMF (10 ml) was stirred at room temperature for24 hrs. The reaction mixture was diluted with water and extracted withethyl acetate. The extract was washed with water and dried. The solventwas evaporated under reduced pressure. The obtained crystals wererecrystallized from tetrahydrofuran-hexane to give the titled compound(0.44 g, 91%).

mp. 135.6-137.0° C.

IR (KBr): 3451, 2939, 2866, 1651, 1643, 1599, 1537, 1471, 1348, 1282,1236, 1060, 790 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.26-1.67 (7H, m), 1.86 (2H, m), 3.68 (2H, m), 4.12(2H, m), 7.29 (1H, m), 7.52-7.55 (2H, m), 7.91 (1H, m), 7.99 (1H, d,J=2.7 Hz), 8.55 (1H, d, J=7.9 Hz), 8.73 (1H, d, J=4.6 Hz).

Elemental Analysis for C₁₉H₂₀N₂O₃S

Calcd. C, 64.02; H, 5.66; N, 7.86.

Found C, 64.03; H, 5.82; N, 7.58.

Example 120

6-(3-Phenylpropoxy)-2-(2-pyridyl)-4H-1,3-benzothiazine-4-on e

A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.35 g,1.3 mmol), 1-bromo-3-phenylpropane (0.86 g, 4.3 mmol) and potassiumcarbonate (0.38 g, 2.7 mmol) and DMF (10 ml) was stirred at roomtemperature for 20 hrs. The reaction mixture was diluted with water andextracted with ethyl acetate. The extract was washed with water anddried. The solvent was evaporated under reduced pressure. The obtainedcrystals were recrystallized from tetrahydrofuran-hexane to give thetitled compound (0.48 g, 92%).

mp. 170.0-170.3° C.

IR (KBr): 3416, 1658, 1651, 1599, 1537, 1342, 1278, 1234 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.17 (2H, tt, J=6.3, 7.5 Hz), 2.84 (2H, t, J=7.5 Hz),4.12 (2H, t, J=6.3 Hz), 7.20-7.32 (6H, m), 7.52-7.55 (2H, m), 7.90 (1H,m), 7.98 (1H, d, J=2.8 Hz), 8.55 (1H, d, J=7.9 Hz), 8.72 (1H, dd, J=0.6,3.9 Hz).

Elemental Analysis for C₂₂H₁₈N₂O₂S

Calcd. C, 70.57; H, 4.85; N, 7.48.

Found C, 70.50; H, 4.83; N, 7.51.

Example 121

6-(Benzyloxy)-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.30 g,1.1 mmol), benzyl bromide (0.61 g, 3.5 mmol) and potassium carbonate(0.32 g, 2.3 mmol) and DMF (10 ml) was stirred at room temperature for 2hrs. The reaction mixture was diluted with water and extracted withethyl acetate. The extract was washed with water and dried. The solventwas evaporated under reduced pressure. The obtained crystals wererecrystallized from tetrahydrofuran-hexane to give the titled compound(0.39 g, 95%).

mp. 198.0-198.8° C.

IR (KBr): 3476, 1649, 1531, 1344, 1278, 1238, 1053, 995, 788 cm⁻¹.

¹H-NMR (CDCl₃) δ: 5.21 (2H, s), 7.35-7.57 (8H, m), 7.90 (1H, m), 8.12(1H, d, J=2.7 Hz), 8.55 (1H, d, J=7.9 Hz), 8.73 (1H, d, J=4.4 Hz).

Elemental Analysis for C₂₀H₁₄N₂O₂S

Calcd. C, 69.35; H, 4.07; N, 8.09.

Found C, 69.34; H, 4.11; N, 8.17.

Example 122

tert-Butyl 2-[[4-oxo-2-(2-pyridyl)-4H-1,3-benzothiazin-6-yl]oxy]acetat e

A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.35 g,1.3 mmol), tert-butyl bromoacetate (0.88 g, 4.5 mmol) and potassiumcarbonate (0.38 g, 2.7 mmol) and DMF (10 ml) was stirred at roomtemperature for 12 hrs. The reaction mixture was diluted with water andextracted with ethyl acetate. The extract was washed with water anddried. The solvent was evaporated. The residue was subjected to a silicagel column chromatography and eluted with hexane-ethyl acetate (1:1,v/v). The obtained crystals were recrystallized fromtetrahydrofuran-hexane to give the titled compound (0.44 g, 87%)

mp. 183.0-184.1° C.

IR (KBr): 2980, 1747, 1658, 1537, 1473, 1280, 1234, 1157, 1078, 792, 738cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.51 (9H, s), 4.67 (2H, s), 7.39 (1H, dd, J=2.8, 8.8Hz), 7.52 (1H, m), 7.57 (1H, d, J=8.8 Hz), 7.90-7.94 (2H, m), 8.53 (1H,dd, J=0.9, 7.9 Hz), 8.72 (1H, m).

Elemental Analysis for C₁₉H₁₈N₂O₄S

Calcd. C, 61.61; H, 4.90; N, 7.56.

Found C, 61.67; H, 4.87; N, 7.54.

Example 123

2-[[4-Oxo-2-(2-pyridyl)-4H-1,3-benzothiazin-6-yl]oxy]acetic acid

A mixture of tert-butyl2-[[4-oxo-2-(2-pyridyl)-4H-1,3-benzothiazin-6-yl]oxy]acetat e (0.30 g,0.81 mmol) and trifluoroacetic acid (10 ml) was stirred at roomtemperature for 3 hrs. The reaction mixture was concentrated underreduced pressure and recrystallized from methanol-diisopropyl ether togive the titled compound (0.17 g, 67%).

mp. 250° C. (decomposed)

IR (KBr): 3069, 1770, 1624, 1601, 1529, 1479, 1427, 1415, 1352, 1238,1082, 831, 790 cm⁻¹.

¹H-NMR (DMSO-d₆) δ: 4.89 (2H, s), 7.50 (1H, dd, J=2.8, 8.8 Hz),7.72-7.78 (2H, m), 7.88 (1H, d, J=8.8 Hz), 8.10 (1H, m), 8.35 (1H, d,J=7.8 Hz), 8.79 (1H, d, J=4.5 Hz), 13.16 (1H, br s).

Elemental Analysis for C₁₅H₁₀N₂O₄S

Calcd. C, 57.32; H, 3.21; N, 8.91.

Found C, 57.34; H, 2.95; N, 8.84.

Example 124

tert-Butyl 6-[[4-oxo-2-(2-pyridyl)-4H-1,3-benzothiazin-6-yl]oxy]hexanoate

A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.50 g,1.9 mmol), tert-butyl 6-bromohexanoate (1.25 g, 4.9 mmol) and potassiumcarbonate (0.54 g, 3.9 mmol) and DMF (10 ml) was stirred at roomtemperature for 24 hrs. The reaction mixture was diluted with water andextracted with ethyl acetate. The extract was washed with water anddried. The solvent was evaporated. The obtained crystals wererecrystallized from ethyl acetate-hexane to give the titled compound(0.75 g, 90%).

mp. 101.2-102.4° C.

IR (KBr): 2937, 2868, 1726, 1658, 1537, 1467, 1342, 1278, 1236, 1151,792 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.52 (2H, m), 1.67 (2H, m), 1.85 (2H,m), 2.26 (2H, t, J=7.2 Hz), 4.12 (2H, t, J=6.4 Hz), 7.29 (1H, dd, J=2.7,8.8 Hz), 7.52-7.55 (2H, m), 7.91 (1H, m), 7.99 (1H, d, J=2.7 Hz), 8.55(1H, d, J=7.8 Hz), 8.72 (1H, d, J=4.7 Hz).

Elemental Analysis for C₂₃H₂₆N₂O₄S

Calcd. C, 64.77; H, 6.14; N, 6.57.

Found C, 64.69; H, 5.98; N, 6.58.

Example 125

6-[[4-Oxo-2-(2-pyridyl)-4H-1,3-benzothiazin-6-yl]oxy]hexano ic acid

A mixture of tert-butyl6-[[4-oxo-2-(2-pyridyl)-4H-1,3-benzothiazin-6-yl]oxy]hexano ate (0.80 g,1.8 mmol) and trifluoroacetic acid (10 ml) was stirred under ice coolingcondition for 1 hr. The reaction mixture was concentrated under reducedpressure and crystallized from diisopropyl ether to give the titledcompound (0.69 g, ca. 100%).

mp. 205.4-206.3° C.

IR (KBr): 3057, 2947, 1711, 1643, 1603, 1523, 1467, 1290, 1236, 1059,802 cm⁻¹.

¹H-NMR (DMSO-d₆) δ: 1.47 (2H, m), 1.59 (2H, m), 1.77 (2H, m), 2.25 (2H,t, J=7.2 Hz), 4.11 (2H, t, J=6.4 Hz), 7.45 (1H, dd, J=2.8, 8.8 Hz),7.72-7.85 (3H, m), 8.10 (1H, m), 8.35 (1H, d, J=7.8 Hz), 8.79 (1H, d,J=4.7 Hz), 12.00 (1H, br s).

Elemental Analysis for C₁₉H₁₈N₂O₄S 0.25H₂O

Calcd. C, 60.87; H, 4.97; N, 7.47.

Found C, 60.75; H, 4.96; N, 7.38.

Reference Example 25

2-Cyano-6-ethylthiopyridine

Ethyl mercaptan (0.49 g, 7.9 mmol) was dissolved in tetrahydrofuran (100ml) and added dropwise to sodium hydride (60% oil, 0.35 g, 8.7 mmol).The reaction mixture was stirred at room temperature for 1 hr. Asolution of 2-chloro-6-cyanopyridine (1.00 g, 7.2 mmol) intetrahydrofuran (10 ml) was added to the mixture, and the mixture wasstirred at room temperature for 18 hrs. The reaction mixture wasconcentrated under reduced pressure, diluted with water and extractedwith ethyl acetate. The extract was washed with saturated brine anddried. The solvent was evaporated under reduced pressure to give thetitled compound (1.02 g, 86%) as an oil.

IR (KBr): 2233, 1576, 1469, 1425, 1267, 1157, 1143, 978, 856, 794 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.38 (3H, t, J=7.4 Hz), 3.20 (2H, q, J=7.3 Hz),7.28-7.36 (2H, m), 7.55 (1H, t, J=7.6 Hz).

Example 126

2-[6-(Ethylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (1.21 g, 7.2 mmol),2-cyano-6-ethylthiopyridine (1.02 g, 6.2 mmol), triethylamine (1.5 ml,10.8 mmol) and toluene (30 ml) was refluxed for 48 hrs. The reactionmixture was concentrated under reduced pressure to give precipitatedcrystals, which were recrystallized from ethanol to give the titledcompound (0.26 g, 14%)

mp. 161.3-162.0° C.

IR (KBr): 1653, 1574, 1525, 1423, 1298, 1284, 1234, 1153, 1124, 1095,981, 812, 725 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.51 (3H, t, J=7.4 Hz), 3.34 (2H, q, J=7.3 Hz),7.35-7.38 (1H, m), 7.61-7.69 (4H, m), 8.18-8.21 (1H, m), 8.53-8.57 (1H,m).

Elemental Analysis for C₁₅H₁₂N₂OS₂

Calcd. C, 59.97; H, 4.03; N, 9.33.

Found C, 60.05; H, 3.85; N, 9.30.

Reference Example 26

2-Cyano-6-isopropylthiopyridine

Isopropyl mercaptan (0.60 g, 7.9 mmol) was dissolved in tetrahydrofuran(100 ml) and added dropwise to sodium hydride (60% oil, 0.35 g, 8.7mmol). The reaction mixture was stirred at room temperature for 1 hr. Asolution of 2-chloro-6-cyanopyridine (1.00 g, 7.2 mmol) intetrahydrofuran (10 ml) was added to the mixture, and the mixture wasstirred at room temperature for 18 hrs. The reaction mixture wasconcentrated under reduced pressure, diluted with water and extractedwith ethyl acetate. The extract was washed with saturated brine anddried. The solvent was evaporated under reduced pressure to give thetitled compound (1.40 g, ca. 100%) as an oil.

IR (KBr): 2233, 1577, 1547, 1425, 1365, 1159, 1143, 1075, 1055, 978,856, 794 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.41 (6H, d, J=6.8 Hz), 4.00-4.15 (1H, m), 7.28-7.35(2H, m), 7.54 (1H, t, J=7.5H).

Example 127

2-[6-(Isopropylthio)-2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (1.21 g, 7.2 mmol),2-cyano-6-isopropylthiopyridine (1.40 g, 7.9 mmol), triethylamine (1.5ml, 10.8 mmol) and toluene (30 ml) was refluxed for 48 hrs. The reactionmixture was concentrated under reduced pressure to give the precipitatedcrystals, which were recrystallized from ethyl acetate-hexane to givethe titled compound (0.24 g, 10%).

mp. 185.4-185.8° C.

IR (KBr): 1658, 1570, 1535, 1429, 1294, 1232, 1141, 1093, 985, 912, 744cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.54 (6H, d, J=6.8 Hz), 4.14-4.23 (1H, m) 7.34 (1H, d,J=8.0 Hz), 7.60-7.71 (4H, m), 8.20 (1H, d, J=7.6 Hz), 8.54-8.57 (1H, m).

Elemental Analysis for C₁₆H₁₄N₂OS₂

Calcd. C, 61.12; H, 4.49; N, 8.91.

Found C, 61.02; H, 4.56; N, 8.91.

Reference Example 27

2-Cyano-6-tert-butylpyridine

tert-Butyl mercaptan (0.72 g, 7.9 mmol) was dissolved in tetrahydrofuran(100 ml) and added dropwise to sodium hydride (60% oil, 0.35 g, 8.7mmol). The reaction mixture was stirred at room temperature for 1 hr. Asolution of 2-chloro-6-cyanopyridine (1.00 g, 7.2 mmol) intetrahydrofuran (10 ml) was added to the mixture, and the mixture wasstirred at room temperature for 18 hrs. The reaction mixture wasconcentrated under reduced pressure, diluted with water and extractedwith ethyl acetate. The extract was washed with saturated brine anddried. The solvent was evaporated under reduced pressure to give thetitled compound (1.19 g, 86%) as an oil.

IR (KBr): 2235, 1574, 1549, 1421, 1361, 1159, 1143, 978, 854, 794 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.59 (9H, s), 7.31-7.38 (2H, m), 7.54 (1H, t, J=7.7Hz).

Example 128

2-[6-(tert-Butylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (1.21 g, 7.2 mmol),2-cyano-6-tert-butylthiopyridine (1.19 g, 6.2 mmol), triethylamine (1.5ml, 10.8 mmol) and toluene (30 ml) was refluxed for 48 hrs. The reactionmixture was concentrated under reduced pressure to give the precipitatedcrystals, which were recrystallized from ethyl acetate-hexane to givethe titled compound (0.15 g, 7%).

mp. 152.9-153.8° C.

IR (KBr): 1660, 1570, 1531, 1427, 1294, 1232, 1136, 1093, 964, 798 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.71 (9H, s), 7.39 (1H, d, J=7.8 Hz), 7.62-7.69 (4H,m), 8.26 (1H, d, J=7.4 Hz), 8.54-8.57 (1H, m).

Elemental Analysis for C₁₇H₁₆N₂OS₂

Calcd. C, 62.16; H, 4.91; N, 8.53.

Found C, 62.07; H, 5.05; N, 8.51.

Reference Example 28

2-Cyano-6-pentylthiopyridine

Pentyl mercaptan (0.83 g, 7.9 mmol) was dissolved in tetrahydrofuran(100 ml) and added dropwise to sodium hydride (60% oil, 0.35 g, 8.7mmol). The reaction mixture was stirred at room temperature for 1 hr. Asolution of 2-chloro-6-cyanopyridine (1.00 g, 7.2 mmol) intetrahydrofuran (10 ml) was added to the mixture, and the mixture wasstirred at room temperature for 18 hrs. The reaction mixture wasconcentrated under reduced pressure, diluted with water and extractedwith ethyl acetate. The extract was washed with saturated brine anddried. The solvent was evaporated under reduced pressure to give thetitled compound (1.48 g, ca. 100%) as an oil.

IR (KBr): 2235, 1574, 1549, 1454, 1427, 1159, 978, 858, 794 cm⁻¹.

¹H-NMR (CDCl₃) δ: 0.92 (3H, t, J=7.0 Hz), 1.38-1.44 (2H, m), 1.69-1.74(2H, m), 3.18 (2H, t, J=7.2 Hz), 7.28-7.35 (2H, m) 7.54 (1H, t, J=7.6Hz).

Example 129

2-[6-(Pentylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (1.21 g, 7.2 mmol),2-cyano-6-pentylthiopyridine (1.48 g, 7.2 mmol), triethylamine (1.5 ml,10.8 mmol) and toluene (30 ml) was refluxed for 48 hrs. The reactionmixture was concentrated under reduced pressure to give the precipitatedcrystals, which were recrystallized from ethyl acetate-hexane to givethe titled compound (1.09 g, 44%).

mp. 105.0-105.1° C.

IR (KBr): 1658, 1572, 1552, 1537, 1431, 1294, 1234, 1145, 1093, 968cm⁻¹.

¹H-NMR (CDCl₃) δ: 0.95 (3H, t, J=7.2 Hz), 1.36-1.52 (2H, m), 1.54-1.59(2H, m), 1.81-1.91 (2H, m), 3.31 (3H, t, J=7.5 Hz), 7.37 (1H, d, J=8.0Hz), 7.58-7.71 (4H, m), 8.19 (1H, d, J=7.5 Hz), 8.54-8.57 (1H, m).

Elemental Analysis for C₁₈H₁₈N₂OS₂

Calcd. C, 63.13; H, 5.30; N, 8.18.

Found C, 63.00; H, 5.42; N, 8.28.

Reference Example 29

2-Cyano-6-isopentylthiopyridine

Isopentyl mercaptan (0.83 g, 7.9 mmol) was dissolved in tetrahydrofuran(100 ml) and added dropwise to sodium hydride (60% oil, 0.35 g, 8.7mmol). The reaction mixture was stirred at room temperature for 1 hr. Asolution of 2-chloro-6-cyanopyridine (1.00 g, 7.2 mmol) intetrahydrofuran (10 ml) was added to the mixture, and the mixture wasstirred at room temperature for 18 hrs. The reaction mixture wasconcentrated under reduced pressure, diluted with water and extractedwith ethyl acetate. The extract was washed with saturated brine anddried. The solvent was evaporated under reduced pressure to give thetitled compound (1.48 g, ca. 100%) as an oil.

IR (KBr): 2233, 1576, 1549, 1466, 1427, 1277, 1159, 1143, 1078, 978,856, 794 cm⁻¹.

¹H-NMR (CDCl₃) δ: 0.96 (6H, d, J=6.5 Hz), 1.55-1.62 (2H, m), 1.69-1.76(1H, m), 3.16-3.21 (2H, m), 7.30-7.35 (2H, m), 7.54 (1H, t, J=7.6 Hz).

Example 130

2-[6-(Isopentylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (1.21 g, 7.2 mmol),2-cyano-6-isopentylthiopyridine (1.48 g, 7.2 mmol), triethylamine (1.5ml, 10.8 mmol) and toluene (30 ml) was refluxed for 48 hrs. The reactionmixture was concentrated under reduced pressure to give the precipitatedcrystals, which were recrystallized from ethyl acetate-hexane to givethe titled compound (0.64 g, 26%).

mp. 103.4-105.1° C.

IR (KBr): 1660, 1570, 1531, 1429, 1294, 1232, 1147, 1093, 1062, 1028,985, 968, 798 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.03 (6H, d, J=6.5 Hz), 1.71-1.80 (2H, m), 1.82-1.91(1H, m), 3.30-3.35 (2H, m), 7.37 (1H, d, J=8.1 Hz), 7.57-7.69 (4H, m),8.18-8.20 (1H, m), 8.54-8.57 (1H, m).

Elemental Analysis for C₁₈H₁₈N₂OS₂

Calcd. C, 63.13; H, 5.30; N, 8.18.

Found C, 62.95; H, 5.08; N, 8.16.

Reference Example 30

2-Cyano-6-(2-phenethylthio)pyridine

2-Phenethyl mercaptan (1.10 g, 7.9 mmol) was dissolved intetrahydrofuran (100 ml) and added dropwise to sodium hydride (60% oil,0.35 g, 8.7 mmol). The reaction mixture was stirred at room temperaturefor 1 hr. A solution of 2-chloro-6-cyanopyridine (1.00 g, 7.2 mmol) intetrahydrofuran (10 ml) was added to the mixture, and the mixture wasstirred at room temperature for 18 hrs. The reaction mixture wasconcentrated under reduced pressure, diluted with water and extractedwith ethyl acetate. The extract was washed with saturated brine anddried. The solvent was evaporated under reduced pressure to give thetitled compound (1.74 g, ca. 100%) as an oil.

IR (KBr): 2233, 1574, 1549, 1494, 1427, 1159, 1143, 978, 912, 856, 794cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.98-3.03 (2H, m), 3.40-3.45 (2H, m), 7.24-7.36 (7H,m), 7.54 (1H, t, J=7.9 Hz).

Example 131

2-[6-(2-Phenethylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-on

A mixture of methyl thiosalicylate (1.21 g, 7.2 mmol),2-cyano-6-(2-phenylthio)pyridine (1.74 g, 7.2 mmol), triethylamine (1.5ml, 10.8 mmol) and toluene (30 ml) was refluxed for 48 hrs. The reactionmixture was concentrated under reduced pressure to give the precipitatedcrystals, which were recrystallized from ethanol to give the titledcompound (1.00 g, 37%).

mp. 167.1-168.4° C.

IR (KBr): 1658, 1570, 1531, 1429, 1296, 1234, 1145, 1093, 1062, 1028,985, 966, 744 cm⁻¹.

¹H-NMR (CDCl₃) δ: 3.14-3.19 (2H, m), 3.57-3.62 (2H, m), 7.25-7.40 (6H,m), 7.51-7.52 (1H, m), 7.62-0.770 (3H, m), 8.20-8.23 (1H, m), 8.53-8.57(1H, m).

Elemental Analysis for C₂₁H₁₆N₂OS₂

Calcd. C, 66.99; H, 4.28; N, 7.44.

Found C, 67.11; H, 4.18; N, 7.38.

Reference Example 31

Methyl 2-cyano-6-pyridylthioaectate

Methyl thioglycolate (0.80 g, 7.5 mmol) was dissolved in tetrahydrofuran(50 ml) and added dropwise to sodium hydride (60% oil, 0.30 g, 7.5mmol). The reaction mixture was stirred at room temperature for 1 hr. Asolution of 2-chloro-6-cyanopyridine (0.70 g, 5.0 mmol) intetrahydrofuran (10 ml) was added to the mixture, and the mixture wasstirred at room temperature for 18 hrs. The reaction mixture wasconcentrated under reduced pressure, diluted with water and extractedwith ethyl acetate. The extract was washed with saturated brine anddried. The solvent was evaporated under reduced pressure. The residuewas subjected to a silica gel column chromatography and eluted withhexane-ethyl acetate (2:1, v/v) to give the titled compound (0.20 g,13%).

IR (KBr): 2235, 1730, 1572, 1554, 1518, 1504, 1433, 1141, 912, 746 cm⁻¹.

¹H-NMR (CDCl₃) δ: 3.79 (3H, s), 3.98 (2H, s), 7.38-7.43 (2H, m) 7.82(1H, t, J=7.9 Hz).

Example 132

Methyl [[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]thio]acetic acid

A mixture of methyl thiosalicylate (0.11 g, 0.67 mmol), methyl2-cyano-6-pyridylthioacetate (0.14 g, 0.67 mmol), triethylamine (0.14ml, 1.00 mmol) and toluene (20 ml) was refluxed for 48 hrs. The reactionmixture was concentrated under reduced pressure to give the precipitatedcrystals, which were recrystallized from methanol to give the titledcompound (0.04 g, 17%).

mp. 117.1° C. (decomposed)

IR (KBr): 1738, 1658, 1572, 1537, 1433, 1296, 1234, 1143, 1095, 912, 744cm⁻¹.

¹H-NMR (CDCl₃) δ: 3.81 (3H, s), 4.14 (2H, s), 7.46 (1H, d, J=8.0 Hz),7.58-7.75 (4H, m), 8.26 (1H, d, J=7.6 Hz), 8.54-8.56 (1H, m).

Elemental Analysis for C₁₆H₁₂N₂O₃S₂

Calcd. C, 55.80; H, 3.51; N, 8.13.

Found C, 55.51; H, 3.51; N, 7.98.

Reference Example 32

2-Cyano-6-[2-(N,N-dimethylamino)ethyl]thiopyridine

2-Dimethylaminoethanethiol (0.71 g, 5.0 mmol) was dissolved intetrahydrofuran (100 ml) and added dropwise to sodium hydride (60% oil,0.44 g, 11.0 mmol). The reaction mixture was stirred at room temperaturefor 1 hr. A solution of 2-chloro-6-cyanopyridine (0.70 g, 5.0 mmol) intetrahydrofuran (10 ml) was added to the mixture, and the mixture wasstirred at room temperature for 18 hrs. The reaction mixture wasconcentrated under reduced pressure, diluted with water and extractedwith ethyl acetate. The extract was washed with saturated brine anddried. The solvent was evaporated under reduced pressure to give thetitled compound (0.49 g, 47%).

IR (KBr): 2233, 1576, 1549, 1456, 1425, 1143, 794 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.32 (6H, s), 2.63 (2H, t, J=7.0 Hz), 3.33 (2H, t,J=7.1 Hz), 7.33-7.36 (2H, m), 7.55 (1H, t, J=7.9 Hz).

Example 133

2-{[6-[2-(N,N-Dimethylamino)ethyl]thio]-2-pyridyl}-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (0.40 g, 2.4 mmol),2-cyano-6-[2-(N,N-dimethylamino)ethyl]thiopyridine (0.49 g, 2.4 mmol),triethylamine (0.50 ml, 3.6 mmol) and toluene (30 ml) was refluxed for48 hrs. The reaction mixture was concentrated under reduced pressure.The residue was subjected to a column chromatography and eluted withethyl acetate-methanol (2:1, v/v). The obtained crystals wererecrystallized from ethyl acetate-hexane to give the titled compound(0.19 g, 23%).

mp. 154.8° C. (decomposed)

IR (KBr): 1655, 1570, 1527, 1431, 1296, 1234, 1095, 985, 912, 744 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.35 (6H, s), 2.77 (2H, t, J=7.0 Hz), 3.47 (2H, t,J=7.3 Hz), 7.39 (1H, d, J=8.0 Hz), 7.58-7.71 (4H, m), 8.19-8.22 (1H, m),8.53-8.56 (1H, m)

Elemental Analysis for C₁₇H₁₇N₃OS₂

Calcd. C, 59.45; H, 4.99; N, 12.23.

Found C, 59.06; H, 4.81; N, 12.04.

Reference Example 33

2-Cyano-6-ethoxypyridine

A mixture of 2-chloro-6-cyanopyridine (1.00 g, 7.2 mmol), sodiumethoxide (0.54 g, 7.9 mmol) and tetrahydrofuran (100 ml) was refluxedfor 18 hrs. The reaction mixture was concentrated under reducedpressure, diluted with ice-water and extracted with ethyl acetate. Theextract was washed with saturated brine and dried. The solvent wasevaporated under reduced pressure. The residue was subjected to a silicagel column chromatography and eluted with hexane-ethyl acetate (5:1,v/v) to give the titled compound (0.15 g, 14%).

IR (KBr): 2235, 1608, 1589, 1564, 1448, 1389, 1334, 1275, 1209, 1163,1111, 1037, 987, 806 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.39 (3H, t, J=7.1 Hz), 4.39 (2H, q, J=7.1 Hz), 6.93(1H, d, J=8.4 Hz), 7.25-7.28 (1H, m), 7.61-7.66 (1H, m).

Example 134

2-(6-Ethoxy-2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (0.17 g, 1.0 mmol),2-cyano-6-ethoxypyridine (0.15 g, 1.0 mmol), triethylamine (0.21 ml, 1.5mmol) and toluene (30 ml) was refluxed for 48 hrs. The reaction mixturewas concentrated under reduced pressure. The residue was subjected to acolumn chromatography and eluted with hexane-ethyl acetate (3:1, v/v).The obtained crystals were recrystallized from ethyl acetate-hexane togive the titled compound (0.04 g, 14%).

mp. 179.5-180.0° C.

IR (KBr): 1651, 1593, 1574, 1523, 1440, 1383, 1332, 1294, 1273, 1238,1095, 1032, 985, 814, 744 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.50 (3H, t, J=7.0 Hz), 4.54 (2H, q, J=7.0 Hz),6.95-6.98 (1H, m), 7.59-7.68 (1H, m), 7.75 (1H, t, J=7.4 Hz), 8.11-8.14(1H, m), 8.53-8.57 (1H, m).

Fab-MS m/z 285.

Example 135

4-Oxo-2-(2-pyridyl)-4H-1,3-benzothiazine-7-carboxylic acid

A mixture of 2-mercaptoterephthalic acid (2.0 g, 10 mmol),2-cyanopyridine (1.3 g, 11 mmol) and pyridine (10 ml) was refluxed for 8hrs. After cooling, the precipitated crystals were collected byfiltration and recrystallized from methanol-diisopropylether to give thetitled compound (1.22 g, 42%).

mp. 294.7-295.1° C.

IR (KBr): 3049, 2665, 2552, 1732, 1697, 1662, 1566, 1535, 1307, 1278,1236, 736 cm⁻¹.

¹H-NMR (DMSO-d₆) δ: 7.77 (1H, m), 8.09-8.17 (2H, m), 8.34-8.44 (3H, m),8.82 (1H, d, J=4.5 Hz), 13.20 (1H, br s).

Elemental Analysis for C₁₄H₈N₂O₃S·1.25H₂O

Calcd. C, 54.81; H, 3.45; N, 9.13.

Found C, 55.02; H, 3.36; N, 9.31.

Example 136

2-(6-Methyl-2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (0.85 g, 5.1 mmol),2-cyano-6-methylpyridine (0.60 g, 5.1 mmol), triethylamine (1.10 ml, 7.9mmol) and toluene (1.1 ml) was refluxed for 9 hrs. After cooling, theprecipitated crystals were collected by filtration and recrystallizedfrom ethanol to give the titled compound (0.71 g, 55%).

mp. 169.8-170.3° C.

IR (KBr): 1651, 1591, 1572, 1531, 1300 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.69 (3H, s), 7.39 (1H, d, J=7.8 Hz), 7.60-7.71 (1H,t, J=7.8 Hz), 8.35 (1H, d, J=7.8 Hz), 8.55 (1H, d, J=7.2 Hz).

Elemental Analysis for C₁₄H₁₀N₂OS

Calcd. C, 66.12; H, 3.96; N, 11.02.

Found C, 65.88; H, 3.69; N, 11.20.

Reference Example 34

2-Cyano-4-phenylpyridine

4-Phenylpyridine N-oxide (3.13 g, 18.3 mmol) was dissolved innitroethane (30 ml), and trimethylsilyl cyanide (2.0 g, 20.2 mmol) andN,N-dimethylcarbamoyl chloride (1.7 ml, 18.5 mmol) were added thereto.The reaction mixture was stirred at room temperature for 45 hrs,concentrated under reduced pressure, combined with saturated aqueoussodium hydrogen carbonate solution and extracted with ethyl acetate. Theextract was washed with saturated brine and dried. The solvent wasevaporated under reduced pressure. The obtained crystals were collectedby filtration, washed with diisopropyl ether and dried to give thetitled compound (2.87 g, 89%).

¹H-NMR (CDCl₃) δ: 7.47-7.65 (5H, m), 7.72 (1H, dd, J=1.8, 5.2 Hz), 7.91(1H, s), 8.75 (1H, d, J=5.1 Hz).

Example 137

2-(4-Phenyl-2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (1.00 g, 5.9 mmol),2-cyano-4-phenylpyridine (1.10 g, 5.9 mmol), triethylamine (1.30 ml, 9.0mmol) and toluene (2.5 ml) was refluxed for 20 hrs. After cooling, theprecipitated crystals were collected by filtration and recrystallizedfrom ethanol to give the titled compound (0.99 g, 53%).

mp. 164.4-164.7° C.

IR (KBr): 1655, 1570, 1533, 1296, 1283 cm⁻¹.

¹H-NMR (CDCl₃) δ: 7.48-7.78 (9H, m), 8.57 (1H, dd, J=2.0, 7.2 Hz), 8.77(1H, d, J=5.1 Hz), 8.80 (1H, s).

Elemental Analysis for C₁₉H₁₂N₂OS

Calcd. C, 72.13; H, 3.82; N, 8.85.

Found C, 72.14; H, 3.82; N, 9.06.

Reference Example 35

2-Cyano-4-methylpyridine

4-Methylpyridine N-oxide (2.0 g, 18.3 mmol) was dissolved in nitroethane(25 ml), and trimethylsilyl cyanide (2.0 g, 20.2 mmol) andN,N-dimethylcarbamoyl chloride (1.7 ml, 18.5 mmol) were added thereto.The reaction mixture was stirred at room temperature for 5 days,concentrated under reduced pressure, combined with saturated aqueoussodium hydrogen carbonate solution and extracted with ethyl acetate. Theextract was washed with saturated brine and dried. The solvent wasevaporated under reduced pressure. The obtained crystals were collectedby filtration, washed with diisopropyl ether and dried to give thetitled compound (0.91 g, 42%).

¹H-NMR (CDCl₃) δ: 2.43 (3H, s), 7.33 (1H, d, J=5.1 Hz), 7.53 (1H, s),8.57 (1H, d, J=4.8 Hz).

Example 138

2-(4-Methyl-2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (1.15 g, 6.8 mmol),2-cyano-4-methylpyridine (0.81 g, 6.8 mmol), triethylamine (1.50 ml,10.8 mmol) and toluene (2.0 ml) was refluxed for 8 hrs. After cooling,the precipitated crystals were collected by filtration andrecrystallized from ethanol to give the titled compound (1.11 g, 64%)

mp. 199.7-199.9° C.

IR (KBr): 1659, 1574, 1537, 1300, 1281 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.48 (3H, s), 7.36 (1H, d, J=4.2 Hz), 7.60-7.72 (3H,m), 8.41 (1H, s), 8.54-8.60 (2H, m).

Elemental Analysis for C₁₄H₁₀N₂OS

Calcd. C, 66.12; H, 3.96; N, 11.02.

Found C, 66.11; H, 3.70; N, 11.29.

Reference Example 36

2-(6-Chloro-2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (0.65 g, 3.9 mmol),2-cyano-6-chloropyridine (0.54 g, 3.9 mmol), triethylamine (1.00 ml, 7.2mmol) and toluene (2.0 ml) was refluxed for 6.5 hrs. After cooling, theprecipitated crystals were collected by filtration and recrystallizedfrom ethanol to give the titled compound (0.39 g, 37%).

mp. 224.3-225.0° C.

IR (KBr): 1664, 1535, 1429, 1298 cm⁻¹.

¹H-NMR (CDCl₃) δ: 7.51-7.74 (4H, m), 7.88 (1H, t, J=7.8 Hz), 8.48 (1H,d, J=7.8 Hz), 8.55 (1H, d, J=7.8 Hz).

Elemental Analysis for C₁₃H₇N₂OSCl

Calcd. C, 56.83; H, 2.57; N, 10.20.

Found C, 56.80; H, 2.38; N, 10.24.

Reference Example 37

5,6,7,8-Tetrahydroquinoline N-oxide

5,6,7,8-Tetrahydroquinoline (3.0 g, 22.5 mmol) was dissolved in ethylacetate (15 ml), and 3-chloroperbenzoic acid (ca. 70%, 5.6 g, 22.5 mmol)was added thereto. The reaction mixture was stirred at room temperaturefor 2 days, subjected to a silica gel column chromatography and elutedwith ethyl acetate-ethanol (5:1, v/v) to give the titled compound (3.4g, 97%).

¹H-NMR (CDCl₃) δ: 1.73-1.95 (4H, m), 2.77 (2H, t, J=6.0 Hz), 2.95 (2H,t, J=6.0 Hz), 6.98-7.06 (2H, m), 8.14 (1H, d, J=5.4 Hz).

Reference Example 38

2-Cyano-5,6,7,8-tetrahydroquinoline

5,6,7,8-Tetrahydroquinoline N-oxide (3.0 g, 19.1 mmol) was dissolved innitroethane (30 ml), and trimethylsilyl cyanide (2.1 g, 21.0 mmol) andN,N-dimethylcarbamoyl chloride (2.1 g, 19.1 mmol) were added thereto.The reaction mixture was stirred at room temperature for 3 days,concentrated under reduced pressure, combined with saturated aqueoussodium hydrogen carbonate solution and extracted with ethyl acetate. Theextract was washed with saturated brine and dried. The solvent wasevaporated under reduced pressure. The residue was subjected to a silicagel column chromatography and eluted with hexane-ethyl acetate (2:1,v/v) to give the titled compound (0.52 g, 17%).

¹H-NMR (CDCl₃) δ: 1.80-1.96 (4H, m), 2.84 (2H, t, J=6.0 Hz), 2.95 (2H,t, J=6.0 Hz), 7.40-7.48 (2H, m).

Example 139

2-(5,6,7,8-Tetrahydro-2-quinolyl)-4H-1,3-benzothiazine-4-on e

A mixture of methyl thiosalicylate (0.43 g, 2.5 mmol),2-cyano-5,6,7,8-tetrahydroquinoline (0.40 g, 2.5 mmol), triethylamine(0.50 ml, 3.8 mmol) and toluene (2.0 ml) was refluxed for 17 hrs. Aftercooling, the precipitated crystals were collected by filtration andrecrystallized from ethanol to give the titled compound (0.22 g, 30%)

mp. 232.3-232.8° C.

IR (KBr): 1659, 1568, 1452, 1421, 1264 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.83-2.00 (4H, m), 2.88 (2H, t, J=6.0 Hz), 3.04 (2H,t, J=6.3 Hz), 7.54-7.67 (4H, m), 8.26 (1H, d, J=7.8 Hz), 8.55 (1H, d,J=7.0 Hz).

Elemental Analysis for C₁₇H₁₄N₂OS

Calcd. C, 69.36; H, 4.79; N, 9.52.

Found C, 69.32; H, 4.89; N, 9.65.

Reference Example 39

2-Cyano-6-ethylpyridine

2-Ethylpyridine N-oxide (3.0 g, 24.4 mmol) was dissolved in nitroethane(30 ml), and trimethylsilyl cyanide (2.4 g, 24.0 mmol) andN,N-dimethylcarbamoyl chloride (2.4 g, 21.9 mmol) were added thereto.The reaction mixture was stirred at room temperature for 3 days,concentrated under reduced pressure, combined with saturated aqueoussodium hydrogen carbonate solution and extracted with ethyl acetate. Theextract was washed with saturated brine and dried. The solvent wasevaporated under reduced pressure. The residue was subjected to a silicagel column chromatography and eluted with hexane-ethyl acetate (2:1,v/v) to give the titled compound (1.0, 31%).

¹H-NMR (CDCl₃) δ: 1.32 (3H, t, J=7.5 Hz), 2.87 (2H, q, J=7.5 Hz), 7.38(1H, d, J=7.8 Hz), 7.52 (1H, d, J=7.5 Hz), 7.73 (1H, t, J=7.8 Hz).

Example 140

2-(6-Ethyl-2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (1.3 g, 7.5 mmol),2-cyano-6-ethylpyridine (0.99 g, 7.5 mmol), triethylamine (1.60 ml, 11.5mmol) and toluene (6.0 ml) was refluxed for 16 hrs. After cooling, theprecipitated crystals were collected by filtration and recrystallizedfrom ethanol to give the titled compound (0.45 g, 22%).

mp. 150.5-150.9° C.

IR (KBr): 1653, 1572, 1533, 1439, 1306 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.42 (3H, t, J=4.6 Hz), 2.95 (2H, q, J=7.6 Hz), 7.39(1H, d, J=7.7 Hz), 7.59-7.70 (3H, m), 7.80 (1H, t, J=7.7 Hz), 8.35 (1H,d, J=7.7 Hz), 8.56 (1H, d, J=5.4 Hz)

Elemental Analysis for C₁₅H₁₂N₂OS

Calcd. C, 67.14; H, 4.51; N, 10.44.

Found C, 67.02; H, 4.42; N, 10.35.

Reference Example 40

tert-Butyl 2-cyano-4-carbamate

4-tert-Butoxycarbonylaminopyridine N-oxide (4.9 g, 23.1 mmol) wasdissolved in nitroethane (60 ml), and trimethylsilyl cyanide (2.5 g,25.4 mmol) and N,N-dimethylcarbamoyl chloride (2.5 g, 23.2 mmol) wereadded thereto. The reaction mixture was stirred at room temperature for3 days, concentrated under reduced pressure, combined with saturatedaqueous sodium hydrogen carbonate solution and extracted with ethylacetate. The extract was washed with saturated brine and dried. Thesolvent was evaporated under reduced pressure. The residue was subjectedto a silica gel column chromatography and eluted with hexane-ethylacetate (2:1, v/v) to give the titled compound (1.7 g, 33%)

¹H-NMR (CDCl₃) δ: 1.54 (9H, s), 6.92 (1H, br s), 7.43 (1H, d, J=5.4 Hz),7.86 (1H, s), 8.49 (1H, d, J=5.7 Hz).

Example 141

tert-Butyl 2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridylcarbamate

A mixture of methyl thiosalicylate (0.61 g, 3.7 mmol),4-tert-butoxycarbonylamino-2-cyanopyridine (0.80 g, 3.7 mmol),triethylamine (0.80 ml, 5.7 mmol) and toluene (2.0 ml) was refluxed for9 hrs. After cooling, the precipitated crystals were collected byfiltration and dried to give the titled compound (0.60 g, 49%).

¹H-NMR (CDCl₃) δ: 1.54 (9H, s), 6.97 (1H, br s), 7.60-7.71 (3H, m), 8.01(1H, d, J=3.3 Hz), 8.18 (1H, s), 8.54-8.57 (2H, m)

Example 142

2-(4-Amino-2-pyridyl)-4H-1,3-benzothiazine-4-one

2-(4-tert-Butoxycarbonylamino-2-pyridyl)-4H-1,3-benzo thiazine-4-one(100 mg, 0.28 mmol) was dissolved in trifluoroacetic acid (2.5 ml) underice cooling condition, and the mixture was stirred for 5 hrs. Thereaction mixture was combined with diisopropyl ether to precipitatecrystals, which were collected by filtration, washed with diethyl etherand dried to give the titled compound (109 mg, 60%).

mp. 207.6-207.9° C.

IR (KBr): 3200, 3119, 1657, 1587, 1529 cm⁻¹.

¹H-NMR (DMSO-d₆) δ: 6.83 (1H, d, J=6.0 Hz), 7.61 (1H, s), 7.70-7.95 (3H,m), 8.17 (1H, d, J=6.0 Hz), 8.37 (1H, d, J=7.8 Hz).

Elemental Analysis for C₁₃H₉N₃OS H₂O

Calcd. C, 46.45; H, 2.72; N, 10.56.

Found C, 46.50; H, 2.86; N, 10.85.

Example 143

2-(4-Cyano-2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (0.65 g, 3.9 mmol),2,4-dicyanopyridine (0.50 g, 3.9 mmol), triethylamine (0.81 ml, 5.8mmol) and toluene (2.0 ml) was refluxed for 2.5 hrs. After cooling, theprecipitated crystals were collected by filtration and recrystallizedfrom acetone-chloroform to give the titled compound (0.54 g, 53%).

mp. 283.4-283.6° C.

IR (KBr): 1655, 1589, 1570, 1529, 1460, 1396 cm⁻¹.

¹H-NMR (CDCl₃) δ: 7.63-7.78 (4H, m), 8.57 (1H, d, J=7.5 Hz), 8.80 (1H,s), 8.93 (1H, d, J=4.8 Hz).

Elemental Analysis for C₁₄H₇N₃OS

Calcd. C, 63.38; H, 2.66; N, 15.84.

Found C, 63.15; H, 2.58; N, 15.63.

Reference Example 41

6-Cyano-N,N-diethylnicotinamide

3-Diethylamidopyridine N-oxide (2.6 g, 13.5 mmol) was dissolved innitroethane (20 ml), and trimethylsilyl cyanide (1.5 g, 14.8 mmol) andN,N-dimethylcarbamoyl chloride (1.5 g, 14.1 mmol) were added thereto.The reaction mixture was stirred at room temperature for 16 hrs,concentrated under reduced pressure, combined with saturated aqueoussodium hydrogen carbonate solution and extracted with ethyl acetate. Theextract was washed with saturated brine and dried. The solvent wasevaporated under reduced pressure. The residue was subjected to a silicagel column chromatography and eluted with hexane-ethyl acetate (1:1,v/v) to give the titled compound (0.36 g, 16%).

¹H-NMR (CDCl₃) δ: 1.15-1.28 (6H, m), 3.24 (2H, m), 3.57 (2H, m), 7.75(1H, d, J=7.8 Hz), 7.85 (1H, d, J=7.8 Hz), 8.72 (1H, s).

Example 144

N,N-Diethyl-6-(4-oxo-4H-1,3-benzothiazin-2-yl)nicotinamide

A mixture of methyl thiosalicylate (0.33 g, 2.0 mmol),2-cyano-5-diethylamidopyridine (0.36 g, 1.8 mmol), triethylamine (0.40ml, 2.9 mmol) and toluene (2.0 ml) was refluxed for 2.5 hrs. Aftercooling, the precipitated crystals were collected by filtration andrecrystallized from ethanol to give the titled compound (0.34 g, 57%).

mp. 193.2-193.3° C.

IR (KBr): 1661, 1626, 1537, 1439, 1284 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.18-1.29 (6H, m), 3.31 (2H, m), 3.60 (2H, m),7.60-7.73 (3H, m), 7.92 (1H, dd, J=1.8, 8.1 Hz), 8.58 (2H, t, J=8.4 Hz),8.75 (1H, s).

Elemental Analysis for C₁₈H₁₇N₃O₂S

Calcd. C, 63.70; H, 5.05; N, 12.38.

Found C, 63.53; H, 4.97; N, 12.22.

Reference Example 42

5-Acetyl-2-cyanopyridine

3-Acetylpyridine N-oxide (2.0 g, 14.6 mmol) was dissolved in nitroethane(20 ml), and trimethylsilyl cyanide (1.7 g, 16.7 mmol) andN,N-dimethylcarbamoyl chloride (1.8 g, 16.7 mmol) were added thereto.The reaction mixture was stirred at room temperature for 16 hrs,concentrated under reduced pressure, combined with saturated aqueoussodium hydrogen carbonate solution and extracted with ethyl acetate. Theextract was washed with saturated brine and dried. The solvent wasevaporated under reduced pressure. The residue was subjected to a silicagel column chromatography and eluted with hexane-ethyl acetate (3:1,v/v) to give the titled compound (0.40 g, 21%).

¹H-NMR (CDCl₃) δ: 2.67 (3H, s), 7.83 (1H, d, J=8.1 Hz), 8.36 (1H, d,J=8.1 Hz), 9.23 (1H, s).

Example 145

2-(5-Acetyl-2-pyridyl)-4H-1,3-benzothiazine-4-one

A mixture of methyl thiosalicylate (0.51 g, 3.0 mmol),3-acetyl-2-cyanopyridine (0.40 g, 2.7 mmol), triethylamine (0.61 ml, 4.4mmol) and toluene (2.0 ml) was refluxed for 20 hrs. After cooling, theprecipitated crystals were collected by filtration and recrystallizedfrom acetone to give the titled compound (0.30 g, 38%)

mp. 276.3-276.7° C.

IR (KBr): 1684, 1651, 1589, 1537 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.71 (3H, s), 7.63-7.75 (3H, m), 8.41 (1H, dd, J=1.8,8.1 Hz), 8.56 (1H, d, J=8.4 Hz), 8.65 (1H, d, J=8.1 Hz), 9.25 (1H, s).

Elemental Analysis for C₁₅H₁₀N₂O₂S

Calcd. C, 63.81; H, 3.57; N, 9.92.

Found C, 63.67; H, 3.49; N, 9.75.

Example 146

Methyl [6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methanesulfon ate

2-(6-Hydroxymethyl-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.54 g, 2.0mmol) and triethylamine (0.31 ml, 2.2 mmol) were dissolved intetrahydrofuran (30 ml). Methanesulfonyl chloride (0.16 ml, 2.1 mmol)was added to the mixture while the mixture was stirred under ice coolingcondition. The reaction mixture was stirred at room temperature for 3hrs, diluted with water and extracted with chloroform. The extract waswashed with water and dried. The solvent was evaporated under reducedpressure. The obtained crystals were recrystallized from ethanol to givethe titled compound (0.64 g, 92%).

mp. 101.9-102.0° C.

IR (KBr): 1653, 1591, 1570, 1531, 1439, 1348, 1300, 1277, 1170, 1022,960, 806, 731 cm⁻¹.

¹H-NMR (CDCl₃) δ: 3.16 (3H, s), 5.46 (2H, s), 7.61-7.74 (4H, m), 7.99(1H, t, J=7.9 Hz), 8.53-8.57 (2H, m).

Elemental Analysis for C₁₅H₁₂N₂O₄S₂

Calcd. C, 51.71; H, 3.47; N, 8.04.

Found C, 51.88; H, 3.63; N, 8.23.

Reference Example 43

tert-Butyl (E)-3-(1-oxido-2-pyridyl)-2-propenoate

tert-Butyl (E)-3-(2-pyridyl)-2-propenoate (2.05 g, 10.0 mmol) wasdissolved in ethyl acetate (10 ml), and 3-chloroperbenzoic acid (ca.70%, 2.35 g, 10.5 mmol) was added thereto. The mixture was stirred atroom temperature overnight. The reaction mixture was subjected to asilica gel (100 g) column chromatography. The fractions eluted withethyl acetate-ethanol (5:1, v/v) were collected and concentrated to givethe title compound (2.14 g, 96%).

IR (KBr): 2980, 1703, 1636, 1609, 1487, 1431, 1323, 1241, 1154 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.53 (9H, s), 6.87 (1H, d, J=16.1 Hz), 7.22-7.28 (2H,m), 7.52 (1H, m), 7.98 (1H, d, J=16.1 Hz), 8.27 (1H, m).

Reference Example 44

tert-Butyl (E)-3-(6-cyano-2-pyridyl)-2-propenoate

tert-Butyl (E)-3-(1-oxido-2-pyridyl)-2-propenoate (2.10 g, 9.5 mmol) wasdissolved in nitroethane (10 ml), and trimethylsilyl cyanide (1.88 g,19.0 mmol) and N,N-dimethylcarbamoyl chloride (2.04 g, 19.0 mmol) wereadded thereto. The reaction mixture was stirred at room temperature for18 hrs and combined with ethyl acetate and water. The organic layer waswashed with saturated aqueous sodium hydrogen carbonate solution anddried over anhydrous magnesium sulfate. The solvent was evaporated. Theresidue was subjected to a silica gel column chromatography. Thefractions eluted with hexane-ethyl acetate (5:1, v/v) were collected andconcentrated to give the titled compound (2.18 g, ca. 100%).

IR (KBr): 2980, 2253, 1713, 1647, 1582, 1471, 1370, 1319, 1152 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.53 (9H, s), 6.93 (1H, d, J=15.6 Hz), 7.54 (1H, d,J=15.6 Hz), 7.57-7.64 (2H, m), 7.84 (1H, t, J=7.8 Hz).

Example 147

tert-Butyl (E)-3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]-2-propenoate

tert-Butyl (E)-3-(6-cyano-2-pyridyl)-2-propenoate (2.32 g, 10.1 mmol)and methyl thiosalicylate (1.86 g, 11.0 mmol) were dissolved in toluene(12 ml), and triethylamine (1.63 g, 25.7 mmol) was added thereto. Thereaction mixture was refluxed for 38 hrs, concentrated, subjected to asilica gel column chromatography and eluted with hexane-ethyl acetate(5:2, v/v) to give the titled compound (0.78 g, 27%) as white crystals.

mp. 175.5-177.6° C.

IR(KBr): 3154, 2980, 1792, 1705, 1659, 1572, 1537, 1454, 1369, 1300cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.59 (9H, s), 7.05 (1H, d, J=15.6 Hz), 7.59-7.70 (5H,m), 7.92 (1H, t, J=7.8 Hz), 8.47-8.60 (2H, m)

Elemental Analysis for C₂₀H₁₈N₂O₃S·0.25H₂O

Calcd. C, 64.76; H, 5.03; N, 7.55.

Found C, 64.64; H, 4.74; N, 7.47.

Example 148

(E)-3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]-2-prop enoic acid

tert-Butyl (E)-3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]-2-propenoate (0.78 g, 2.0 mmol) was dissolved in trifluoroacetic acid (4.0 ml)under ice cooling condition. The reaction mixture was stirred for 1 hrwhile it was warmed gradually to room temperature. The reaction mixturewas concentrated under reduced pressure to precipitate crystals, whichwere recrystallized from methanol-diisopropyl ether to give the titledcompound (0.60 g, 97%) as white crystals.

mp. 115.6-115.7° C.

IR(KBr): 3214, 1715, 1647, 1572, 1534, 1443, 1385, 1308, 1225, 1101, 972cm⁻¹.

¹H-NMR (DMSO-d₆) δ: 7.05 (1H, d, J=15.7 Hz), 7.71-7.77 (2H, m), 7.85(1H, m), 7.99-8.08 (2H, m), 8.18 (1H, t, J=7.7 Hz), 8.33-8.39 (2H, m).

Elemental Analysis for C₁₆H₁₀N₂O₃S·0.25H₂O

Calcd. C, 61.04; H, 3.36; N, 8.90.

Found C, 61.37; H, 3.17; N, 8.94.

Example 149

2-[6-(Ethylsulfinyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one

2-[6-(Ethylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-on e (0.10 g, 0.33mmol) was dissolved in chloroform (50 ml). A solution of3-chloroperbenzoic acid (ca. 77%, 0.075 g, 0.33 mmol) in chloroform (10ml) was added dropwise to the mixture, and the mixture was stirred atroom temperature for 1 hr. The solvent was evaporated and the residuewas recrystallized from ethanol to give the titled compound (0.050 g,47%) as pale yellow crystals.

mp. 181.5-182.1° C.

IR(KBr): 1662, 1585, 1570, 1533, 1437, 1412, 1311, 1277, 1255, 1230,1145, 1118, 1095, 1076, 1062, 993, 785, 758, 733 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.29 (3H, t, J=7.3 Hz), 3.00-3.12 (1H, m), 3.25-3.37(1H, m), 7.61-7.74 (3H, m), 8.16-8.25 (2H, m), 8.55-8.61 (2H, m).

IR(KBr): 1658, 1572, 1537, 1439, 1296, 1249, 1053, 1028, 912, 746 cm⁻¹.

Elemental Analysis for C₁₅H₁₂N₂O₂S₂

Calcd. C, 56.94; H, 3.82; N, 8.85.

Found C, 56.88; H, 3.74; N, 8.83.

Example 150

2-[6-(Ethylsulfonyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one

2-[6-(Ethylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-on e (0.10 g, 0.33mmol) was dissolved in chloroform (30 ml). A solution of3-chloroperbenzoic acid (ca. 77%, 0.15 g, 0.66 mmol) in chloroform (10ml) was added dropwise to the mixture, and the mixture was stirred atroom temperature for 3 hrs. The solvent was evaporated and the residuewas recrystallized from ethanol to give the titled compound (0.020 g,19%) as pale yellow crystals.

mp. 201.5-203.0° C.

IR(KBr): 1662, 1585, 1570, 1533, 1437, 1412, 1311, 1277, 1255, 1230,1145, 1118, 1095, 1076, 1062, 993, 785, 758, 733 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.43 (3H, t, J=7.4 Hz), 3.57 (1H, q, J=7.4 Hz),7.63-7.76 (3H, m), 8.21 (1H, t, J=7.9 Hz), 8.31-8.34 (1H, m), 8.55-8.58(1H, m), 8.76-8.78 (1H, m).

Elemental Analysis for C₁₅H₁₂N₂O₃S₂

Calcd. C, 54.20; H, 3.64; N, 8.43.

Found C, 54.22; H, 3.63; N, 8.49.

Example 151

2-[6-(Isopropylsulfinyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one

2-[6-(Isopropylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-one (0.09 g, 0.29mmol) was dissolved in chloroform (50 ml). A solution of3-chloroperbenzoic acid (ca. 77%, 0.064 g, 0.29 mmol) in chloroform (10ml) was added dropwise to the mixture, and the mixture was stirred atroom temperature for 1 hr. The solvent was evaporated and the residuewas recrystallized from ethanol to give the titled compound (0.056 g,59%) as pale yellow crystals.

mp. 166.3-166.0° C.

IR(KBr): 1666, 1572, 1537, 1435, 1298, 1246, 1298, 1246, 1095, 1055,1028, 736 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.11 (3H, d, J=6.8 Hz), 1.51 (3H, d, J=7.0 Hz),3.27-3.38 (1H, m), 7.61-7.74 (3H, m), 8.15-8.22 (2H, m), 8.55-8.61 (2H,m).

Elemental Analysis for C₁₆H₁₄N₂O₂S₂

Calcd. C, 58.16; H, 4.27; N, 8.48.

Found C, 58.16; H, 4.17; N, 8.37.

Example 152

2-[6-(Isopropylsulfonyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one

2-[6-(Isopropylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-one (0.10 g, 0.32mmol) was dissolved in chloroform (30 ml).

A solution of 3-chloroperbenzoic acid (ca. 77%, 0.14 g, 0.64 mmol) inchloroform (10 ml) was added dropwise to the mixture, and the mixturewas stirred at room temperature for 3 hr. The solvent was evaporated andthe residue was recrystallized from ethanol to give the titled compound(0.027 g, 25%) as pale yellow crystals.

mp. 205.0-206.0° C.

IR(KBr): 1662, 1570, 1535, 1439, 1298, 1118, 1095, 1062, 993, 733 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.44 (6H, d, J=6.9 Hz), 3.87 (1H, q, J=6.9 Hz),7.65-7.74 (3H, m), 8.20 (1H, t, J=7.8 Hz), 8.31-8.34 (1H, m), 8.56-8.58(1H, m), 8.75-8.78 (1H, m).

Elemental Analysis for C₁₆H₁₄N₂O₃S₂

Calcd. C, 55.47; H, 4.07; N, 8.09.

Found C, 55.27; H, 4.12; N, 8.00.

Example 153

2-[6-(tert-Butylsulfinyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one

2-[6-(tert-Butylthio)-2-pyridyl]-4H-1,3-benzothiazine -one (0.15 g, 0.46mmol) was dissolved in chloroform (30 ml), and a solution of3-chloroperbenzoic acid (ca. 77%, 0.10 g, 0.46 mmol) in chloroform (10ml) was added dropwise thereto. The reaction mixture was stirred at roomtemperature for 1 hr. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the titled compound (0.12 g, 75%) aswhite crystals.

mp. 180.5° C. (decomposed)

IR(KBr): 1666, 1572, 1537, 1433, 1298, 1244, 1095, 1047, 736 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.32 (9H, s), 7.63-7.71 (3H, m), 8.14 (1H, t, J=7.9Hz), 8.22-8.25 (1H, m), 8.55-8.62 (2H, m).

Elemental Analysis for C₁₇H₁₆N₂O₂S₂

Calcd. C, 59.28; H, 4.68; N, 8.13.

Found C, 59.14; H, 4.84; N, 8.17.

Example 154

2-[6-(tert-Butylsulfonyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one

2-[6-(tert-Butylthio)-2-pyridyl]-4H-1,3-benzothiazine -4-one (0.15 g,0.46 mmol) was dissolved in chloroform (50 ml), and a solution of3-chloroperbenzoic acid (ca. 77%, 0.21 g, 0.92 mmol) in chloroform (10ml) was added dropwise thereto. The reaction mixture was stirred at roomtemperature for 3 hrs. The solvent was evaporated and the residue wasrecrystallized from ethanol to give the titled compound (0.11 g, 67%) aspale yellow crystals.

mp. 233.6-234.7° C.

IR(KBr): 1657, 1572, 1529, 1466, 1433, 1298, 1248, 1105, 1064, 993, 748cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.52 (9H, s), 7.64-7.75 (3H, m), 8.19 (1H, t, J=7.9Hz), 8.33-8.35 (1H, m), 8.55-8.58 (1H, m), 8.76-8.79 (1H, m).

Elemental Analysis for C₁₇H₁₆N₂O₃S₂

Calcd. C, 56.65; H, 4.47; N, 7.77.

Found C, 56.71; H, 4.34; N, 7.83.

Example 155

2-[6(n-Pentylsulfinyl)-2-pyridyl]-4H-1,3-benzothiazine-4-on e

2-[6-(n-Pentylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-one (0.15 g, 0.44mmol) was dissolved in chloroform (50 ml), and a solution of3-chloroperbenzoic acid (ca. 77%, 0.10 g, 0.46 mmol) in chloroform (10ml) was added dropwise thereto. The reaction mixture was stirred at roomtemperature for 1 hr. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the titled compound (0.075 g, 48%)as white crystals.

mp. 146.0-147.0° C.

IR(KBr): 1660, 1572, 1537, 1433, 1298, 1242, 1093, 1039, 1028, 991, 748cm⁻¹.

¹H-NMR (CDCl₃) δ: 0.90 (3H, t, J=7.0 Hz), 1.33-1.49 (5H, m), 1.90-1.99(1H, m), 2.97-3.06 (1H, m), 3.17-3.27 (1H, m), 7.61-7.74 (3H, m),8.13-8.26(2H, m), 8.58 (2H, t, J=8.1 Hz).

Elemental Analysis for C₁₈H₁₈N₂O₂S₂

Calcd. C, 60.31; H, 5.06; N, 7.81.

Found C, 60.01; H, 5.01; N, 7.82.

Example 156

2-[6-(n-Pentylsulfonyl)-2-pyridyl]-4H-1,3-benzothiazine-4-o ne

2-[6-(n-Pentylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-one (0.30 g, 0.88mmol) was dissolved in chloroform (50 ml), and a solution of3-chloroperbenzoic acid (ca. 77%, 0.39 g, 1.75 mmol) in chloroform (10ml) was added dropwise thereto. The reaction mixture was stirred at roomtemperature for 3 hrs. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the titled compound (0.15 g, 44%) aswhite crystals.

mp. 160.0-161.0° C.

IR(KBr): 1660, 1587, 1572, 1537, 1462, 1439, 1408, 1302, 1278, 1249,1095, 1064, 1028, 993, 752 cm⁻¹.

¹H-NMR (CDCl₃) δ: 0.90 (3H, t, J=7.1 Hz), 1.32-1.51 (4H, m),1.81-1.91(2H, m), 3.50-3.55 (2H, m), 7.65-7.74 (3H, m), 8.21 (1H, t,J=7.8 Hz), 8.30-8.33(1H, m), 8.56-8.59 (1H, m) 8.75-8.78 (1H, m).

Elemental Analysis for C₁₈H₁₈N₂O₃S₂

Calcd. C, 57.73; H, 4.84; N, 7.48.

Found C, 57.75; H, 4.87; N, 7.51.

Example 157

2-(6-Isoamylsulfinyl-2-pyridyl)-4H-1,3-benzothiazine-4-one

2-[6-(Isoamylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-one (0.15 g, 0.44mmol) was dissolved in chloroform (50 ml), and a solution of3-chloroperbenzoic acid (ca. 77%, 0.10 g, 0.46 mmol) in chloroform (10ml) was added dropwise thereto. The reaction mixture was stirred at roomtemperature for 1 hr. The solvent was evaporated, and the residue wasrecrystallized from hexane-ethyl acetate to give the titled compound(0.15 g, 96%) as pale yellow amorphous.

mp. 59.5-61.0° C.

¹H-NMR (CDCl₃) δ: 0.94 (6H, t, J=6.8 Hz), 1.37-1.47 (1H, m) 1.74-1.77(1H, m), 1.83-1.91 (1H, m), 3.01-3.09 (1H, m), 3.21-3.29 (1H, m),7.61-7.74 (3H, m), 8.16 (2H, t, J=7.8 Hz), 8.24-8.26(1H, m), 8.56-8.61(2H, m).

IR(KBr): 1666, 1591, 1572, 1537, 1437, 1300, 1246, 1126, 1095, 1049,1030, 993, 743 cm⁻¹.

Fab Mass(M+1)=359.0 (theoretical value)=359.1

Example 158

2-(6-Isoamylsulfonyl-2-pyridyl)-4H-1,3-benzothiazine-4-one

2-(6-Isoamylthio-2-pyridyl)-4H-1,3-benzothiazine-4-on e (0.30 g, 0.88mmol) was dissolved in chloroform (50 ml), and a solution of3-chloroperbenzoic acid (ca. 77%, 0.39 g, 1.75 mmol) in chloroform (10ml) was added dropwise thereto. The reaction mixture was stirred at roomtemperature for 3 hrs. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the titled compound (0.10 g, 31%) aspale yellow crystals.

mp. 145.5-147.0° C.

IR(KBr): 1666, 1591, 1572, 1537, 1440, 1302, 1126, 1095, 1062, 1030,995, 743 cm⁻¹.

¹H-NMR (CDCl₃) δ: 0.96 (6H, d, J=5.8 Hz), 1.71-1.75 (2H, m) 3.52-3.57(2H, m), 7.63-7.76 (3H, m), 8.21 (1H, t, J=7.7 Hz), 8.30-8.33(1H, m),8.55-8.59 (1H, m), 8.77 (1H, d, J=7.8 Hz).

Elemental Analysis for C₁₈H₁₈N₂O₃S₂

Calcd. C, 57.73; H, 4.84; N, 7.48.

Found C, 57.63; H, 4.86; N, 7.51.

Reference Example 45

2-Benzylthio-6-cyanopyridine

Benzyl mercaptan (0.99 g, 7.94 mmol) and sodium hydride (60% in oil,0.35 g, 8.66 mmol) were added to THF (30 ml), and the mixture wasstirred at room temperature for 1 hr. A solution of2-chloro-6-cyanopyridine (1.00 g, 7.22 mmol) in THF (10 ml) was addeddropwise to the reaction mixture, and the mixture was stirred at roomtemperature for 18 hrs. The reaction mixture was combined with ethylacetate and brine. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated togive the titled compound (1.63 g, 100%) as a pale pink oil.

IR(KBr): 2233, 1574, 1494, 1452, 1427, 1271, 1159, 1141, 912, 794 cm⁻¹.

¹H-NMR (CDCl₃) δ: 4.42 (2H, s), 7.25-7.43 (7H, m), 7.54 (1H, t, J=7.9Hz).

Example 159

2-(6-Benzylthio-2-pyridyl)-4H-1,3-benzothiazine-4-one

2-Benzylthio-6-cyanopyridine (1.63 g, 7.22 mmol) and methylthiosalicylate (1.21 g, 7.22 mmol) were dissolved in toluene (30 ml),and triethylamine (1.52 ml, 10.8 mmol) was added thereto. The reactionmixture was refluxed for 48 hrs. The solvent was evaporated and theresidue was recrystallized from ethanol to give the titled compound(1.03 g, 44%) as white crystals.

mp. 227.0-228.0° C.

IR(KBr): 1651, 1572, 1537, 1431, 1302, 1288, 1234, 1147, 1097, 1066,987, 972, 794 cm⁻¹.

¹H-NMR (CDCl₃) δ: 4.62 (2H, s), 7.25-7.39 (4H, m), 7.48-7.51 (2H, m),7.60-7.70 (4H, m), 8.22-8.24 (1H, m), 8.54-8.56 (1H, m)

Elemental Analysis for C₂₀H₁₄N₂OS₂

Calcd. C, 66.27; H, 3.86; N, 7.73.

Found C, 66.06; H, 3.92; N, 7.69.

Example 160

2-(6-Benzylsulfinyl-2-pyridyl)-4H-1,3-benzothiazine-4-one

2-(6-Benzylthio-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.18 g, 0.50mmol) was dissolved in chloroform (30 ml), and a solution of3-chloroperbenzoic acid (ca. 77%, 0.11 g, 0.50 mmol) in chloroform (10ml) was added dropwise thereto. The reaction mixture was stirred at roomtemperature for 1 hr. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the titled compound (0.057 g, 30%)as pale yellow crystals.

mp. 208.5-210.0° C.

IR(KBr): 1660, 1572, 1537, 1435, 1298, 1246, 1095, 1051, 1030, 912, 733cm⁻¹.

¹H-NMR (CDCl₃) δ: 4.22, 4.47 (2H, q_(AB), J=13.2 Hz), 6.99-7.03 (2H, m),7.22-7.26 (3H, m), 7.67-7.72 (3H, m), 7.79-7.82 (1H, m), 7.97 (1H, t,J=7.8 Hz), 8.53-8.57 (2H, m)

Elemental Analysis for C₂₀H₁₄N₂O₂S₂·0.25H₂O

Calcd. C, 62.73; H, 3.82; N, 7.31.

Found C, 62.68; H, 3.88; N, 7.32.

Example 161

2-[6-(Benzylsulfonyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one

2-[6-(Benzylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-o ne (0.30 g, 0.83mmol) was dissolved in chloroform (30 ml), and a solution of3-chloroperbenzoic acid (ca. 70%, 0.41 g, 1.66 mmol) in chloroform (10ml) was added dropwise thereto. The reaction mixture was stirred at roomtemperature for 3 hrs. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the titled compound (0.10 g, 30%) aspale yellow crystals.

mp. 217.0-218.0° C.

IR(KBr): 1660, 1570, 1531, 1439, 1300, 1168, 1116, 1095, 1062, 1030,993, 733 cm⁻¹.

¹H-NMR (CDCl₃) δ: 4.79 (2H, s), 7.22-7.28 (5H, m), 7.70-7.76 (3H, m),8.03-8.06 (2H, m), 8.58-8.60(1H, m), 8.70-8.73 (1H, m).

Elemental Analysis for C₂₀H₁₄N₂O₃S₂

Calcd. C, 60.90; H, 3.58; N, 7.10.

Found C, 60.78; H, 3.87; N, 7.22.

Example 162

2-[6-(2-Phenylethylsulfinyl)-2-pyridyl]-4H-1,3-benzothiazin e-4-one

2-[6-(Phenylethylthio)-2-pyridyl]-4H-1,3-benzothiazin e-4-one (0.18 g,0.48 mmol) was dissolved in chloroform (30 ml), and a solution of3-chloroperbenzoic acid (ca. 77%, 0.11 g, 0.48 mmol) in chloroform (10ml) was added dropwise thereto. The reaction mixture was stirred at roomtemperature for 1 hr. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the titled compound (0.14 g, 75%) aspale yellow crystals.

mp. 164.5-165.5° C.

IR(KBr): 1664, 1572, 1537, 1433, 1298, 1246, 1095, 1049, 1030, 912, 746cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.89-2.94 (1H, m), 3.23-3.39 (2H, m), 3.48-3.53 (1H,m), 7.18-7.24 (5H, m), 7.63-7.72 (3H, m), 8.14 (1H, t, J=7.8 Hz),8.23-8.26 (1H, m), 8.55-8.59 (2H, m).

Elemental Analysis for C₂₁H₁₆N₂O₂S₂

Calcd. C, 64.26; H, 4.11; N, 7.14.

Found C, 63.99; H, 4.00; N, 7.07.

Example 163

2-[6-(2-Phenylethyl)sulfonyl-2-pyridyl]-4H-1,3-benzothiazin e-4-one

2-[6-(2-Phenylethyl)thio-2-pyridyl]-4H-1,3-benzothiaz ine-4-one (0.30 g,0.80 mmol) was dissolved in chloroform (30 ml), and a solution of3-chloroperbenzoic acid (ca. 70%, 0.39 g, 1.59 mmol) in chloroform (10ml) was added dropwise thereto. The reaction mixture was stirred at roomtemperature for 3 hrs. The solvent was evaporated, and the residue wasrecrystallized from hexane-ethyl acetate to give the titled compound(0.014 g, 4%) as pale yellow crystals.

mp. 161.5-163.5° C.

IR(KBr): 1653, 1568, 1558, 1531, 1437, 1302, 1168, 1118, 1095, 1062,1030, 993, 742 cm⁻¹.

¹H-NMR (CDCl₃) δ: 3.17-3.23 (2H, m), 3.84-3.89 (2H, m), 7.17-7.33 (5H,m), 7.61-7.74 (3H, m), 8.14 (1H, t, J=7.7 Hz), 8.23-8.26 (1H, m), 8.58(1H, d, J=7.5 Hz), 8.71 (1H, d, J=7.8 Hz).

Elemental Analysis for C₂₁H₁₆N₂O₃S₂·0.5H₂O

Calcd. C, 60.41; H, 4.10; N, 6.70.

Found C, 60.58; H, 4.06; N, 6.60.

Reference Example 46

2-Cyano-6-(3-phenylpropylthio)pyridine

3-Phenylpropylmercaptan (1.21 g, 7.94 mmol) and sodium hydride (60%,0.35 g, 8.66 mmol) were added to THF (30 ml), and the mixture wasstirred at room temperature for 1 hr. A solution of2-chloro-6-cyanopyridine (1.00 g, 7.22 mmol) in THF (10 ml) was addeddropwise to the mixture and the mixture was stirred at room temperaturefor 18 hrs. The reaction mixture was combined with ethyl acetate andwater. The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated to give thetitled compound (1.84 g, 100%).

IR(KBr): 2233, 1693, 1576, 1556, 1494, 1485, 1452, 1427, 1377, 1278,1143, 978, 796 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.00-2.10 (2H, m), 2.77 (2H, t, J=7.3 Hz), 3.18 (2H,t, J=7.16 Hz), 7.16-7.35 (5H, m), 7.53 (1H, t, J=7.6 Hz)

Example 164

2-[6-(3-Phenylpropylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-one

2-Cyano-6-(3-phenylpropylthio)pyridine (1.84 g, 7.22 mmol) and methylthiosalicylate (1.21 g, 7.22 mmol) were dissolved in toluene (30 ml),and triethylamine (1.52 ml, 10.8 mmol) was added thereto. The reactionmixture was refluxed for 48 hrs. The solvent was evaporated and theresidue was recrystallized from ethanol to give the titled compound(1.06 g, 38%) as pale yellow crystals.

mp. 192.5-194.0° C.

IR(KBr): 1647, 1639, 1570, 1525, 1431, 1298, 1238, 1145, 1095, 1064,985, 970, 742 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.14-2.24 (2H, m), 2.89 (2H, t, J=7.4 Hz), 3.35 (2H,t, J=7.4 Hz), 7.22-7.28(5H, m), 7.36-7.39 (1H, m), 7.57-7.69 (1H, m),8.18-8.21 (1H, m), 8.54-8.57 (1H, m).

Elemental Analysis for C₂₂H₁₈N₂OS₂

Calcd. C, 67.66; H, 4.65; N, 7.17.

Found C, 67.58; H, 4.67; N, 7.21.

Example 165

2-[6-[(3-Phenylpropyl)sulfinyl]-2-pyridyl]-4H-1,3-benzothia zine-4-one

2-[6-(3-Phenylpropyl)thio-2-pyridyl]-4H-1,3-benzothia zine-4-one (0.20g, 0.50 mmol) was dissolved in chloroform (30 ml), and a solution of3-chloroperbenzoic acid (ca. 70%, 0.11 g, 0.50 mmol) in chloroform (10ml) was added dropwise thereto. The reaction mixture was stirred at roomtemperature for 1 hr. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the titled compound (0.063 g, 31%)as pale yellow crystals.

mp. 164.5-165.5° C.

IR(KBr): 1658, 1572, 1537, 1433, 1400, 1298, 1246, 1095, 1051, 1030,912, 746 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.91-1.96 (1H, m), 2.31-2.34 (1H, m), 2.76-2.85 (2H,m), 3.01-3.07 (1H, m), 3.23-3.31 (1H, m), 7.13-7.26 (5H, m), 7.52-7.75(3H, m), 8.12-8.24 (2H, m), 8.56-8.59 (2H, m).

Elemental Analysis for C₂₂H₁₈N₂O₂S₂·0.5H₂O

Calcd. C, 63.59; H, 4.61; N, 6.74.

Found C, 63.33; H, 4.58; N, 6.78.

Example 166

2-[6-[(3-Phenylpropyl)sulfonyl]-2-pyridyl]-4H-1,3-benzothia zine-4-one

2-[6-(3-Phenylpropyl)thio-2-pyridyl]-4H-1,3-benzothia zine-4-one (0.30g, 0.77 mmol) was dissolved in chloroform (30 ml), and a solution of3-chloroperbenzoic acid (ca. 70%, 0.38 g, 1.54 mmol) in chloroform (10ml) was added dropwise thereto. The reaction mixture was stirred at roomtemperature for 3 hrs. The solvent was evaporated, and the residue wasrecrystallized from n-hexane-ethyl acetate to give the titled compound(0.063 g, 19%) as pale yellow crystals.

mp. 149.5-151.0° C.

IR(KBr): 1658, 1572, 1535, 1439, 1300, 1118, 1095, 1062, 993, 912, 746cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.15-2.25 (2H, m), 2.81 (2H, t, J=6.4 Hz), 3.50-3.55(2H, m), 7.13-7.16 (3H, m), 7.22-7.26 (3H, m), 7.58-7.61(1H, m),7.68-7.75 (2H, m), 8.19 (1H, t, J=7.8 Hz), 8.30 (1H, d, J=7.7 Hz),8.56-8.59 (1H, m), 8.75 (1H, d, J=7.8 Hz).

Elemental Analysis for C₂₂H₁₈N₂O₃S₂·0.25H₂O

Calcd. C, 61.88; H, 4.36; N, 6.56.

Found C, 62.01; H, 4.25; N, 6.60.

Example 167

2-(6-Methylthiomethyl-2-pyridyl)-4H-1,3-benzothiazine-4-one

[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methane sulfonate (0.55 g,1.58 mmol) was dissolved in DMF (30 ml), and sodium thiomethoxide (0.13g, 1.74 mmol) was added thereto. The mixture was stirred at 70° C. for 3hrs. The reaction mixture was combined with ethyl acetate and water. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated. The residue wasrecrystallized from ethanol to give the titled compound (0.35 g, 75%) aspale yellow crystals.

mp. 151.5-153.0° C.

IR(KBr): 1658, 1589, 1572, 1531, 1439, 1300, 1277, 1234, 1095, 993, 744cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.17 (3H, s), 3.90 (2H, s), 7.59-7.74(4H, m), 7.88(1H, t, J=7.8 Hz), 8.42 (1H, d, J=7.7 Hz), 8.56 (1H, d, J=8.5 Hz).

Elemental Analysis for C₁₅H₁₂N₂OS₂

Calcd. C, 59.97; H, 4.03; N, 9.33.

Found C, 59.87; H, 3.94; N, 9.39.

Example 168

2-(6-Methylsulfinylmethyl-2-pyridyl)-4H-1,3-benzothiazine-4-one

2-(6-Mehtylthiomethyl-2-pyridyl)-4H-1,3-benzothiazine -4-one (0.10 g,0.33 mmol) was dissolved in chloroform (50 ml), and a solution of3-chloroperbenzoic acid (ca. 77%, 0.075 g, 0.33 mmol) in chloroform (10ml) was added dropwise thereto. The reaction mixture was stirred at roomtemperature for 1 hr. The solvent was evaporated, and the residue wasrecrystallized from ethyl acetate to give the titled compound (0.052 g,50%) as pale yellow crystals.

mp. 184.5-185.5° C.

IR(KBr): 1651, 1568, 1531, 1454, 1435, 1298, 1278, 1234, 1095, 1028,995, 744 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.68 (3H, s), 4.21, 4.32 (2H, q_(AB), J=12.8 Hz),7.59-7.70 (4H, m), 7.94 (1H, t, J=7.8 Hz), 8.51-8.57 (2H, m)

Elemental Analysis for C₁₅H₁₂N₂O₂S₂·0.25H₂O

Calcd. C, 56.14; H, 3.92; N, 8.73.

Found C, 56.43; H, 3.74; N, 8.86.

Example 169

2-(6-Methylsulfonylmethyl-2-pyridyl)-4H-1,3-benzothiazine-4-one

2-(6-Methylthiomethyl-2-pyridyl)-4H-1,3-benzothiazine -4-one (0.12 g,0.40 mmol) was dissolved in chloroform (50 ml), and a solution of3-chloroperbenzoic acid (ca. 77%, 0.18 g, 0.80 mmol) in chloroform (10ml) was added dropwise thereto. The reaction mixture was stirred at roomtemperature for 3 hrs. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the titled compound (0.065 g, 49%)as white crystals.

mp. 230.5-231.5° C.

IR(KBr): 1655, 1570, 1533, 1439, 1302, 1114, 1097, 995, 738 cm⁻¹.

¹H-NMR (CDCl₃) δ: 3.05 (3H, s), 4.55 (2H, s), 7.60-7.74 (4H, m) 8.00(1H, t, J=7.7 Hz), 8.54-8.59 (2H, m).

Elemental Analysis for C₁₅H₁₂N₂O₃S₂

Calcd. C, 54.20; H, 3.64; N, 8.43.

Found C, 53.95; H, 3.62; N, 8.38.

Example 170

2-[6-(4-Morpholinomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one

[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methane sulfonate (0.10 g,0.29 mmol) was dissolved in DMF (30 ml), and triethylamine (0.07 ml,0.48 mmol) and morpholine (0.028 g, 0.32 mmol) were added thereto. Thereaction mixture was stirred at 70° C. for 9 hrs and combined with ethylacetate and water. The organic layer was washed with brine and driedover anhydrous magnesium sulfate. The solvent was evaporated and theresidue was recrystallized from ethanol to give the titled compound(0.052 g, 53%) as white crystals.

mp. 191.8° C. (decomposed)

IR(KBr): 1660, 1591, 1572, 1537, 1439, 1294, 1267, 1234, 1114, 1097,1066, 995, 738 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.59-2.62 (4H, m), 3.71-3.79 (4H, m), 3.81 (2H, s),7.60-7.73 (4H, m), 7.88 (1H, t, J=7.7 Hz), 8.42 (1H, d, J=7.7 Hz),8.54-8.57 (1H, m).

Elemental Analysis for C₁₈H₁₇N₃O₂S

Calcd. C, 63.70; H, 5.05; N, 12.38.

Found C, 63.96; H, 5.21; N, 12.14.

Reference Example 47

5-Cyano-2-methylthiopyridine

2-Chloro-5-cyanopyridine (2.10 g, 15.1 mmol) and sodium thiomethoxide(1.16 g, 16.5 mmol) were added to THF (30 ml). The reaction mixture wasrefluxed for 9 hrs and combined with ethyl acetate and water. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated to give the titledcompound (2.26 g, 100%) as pale yellow crystals.

IR(KBr): 2229, 1585, 1533, 1460, 1363, 1113, 912, 742 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.59 (3H, s), 7.24-7.27 (1H, m), 7.64-7.67 (1H, m),8.66-8.67 (1H, m).

Example 171

2-[6-(Methylthio)-3-pyridyl]-4H-1,3-benzothiazine-4-one

5-Cyano-2-methylthiopyridine (2.26 g, 15.0 mmol) and methylthiosalicylate (5.05 g, 30.0 mmol) were dissolved in toluene (100 ml),and triethylamine (6.3 ml, 45.0 mmol) was added thereto. The reactionmixture was refluxed for 48 hrs. The solvent was evaporated. The residuewas recrystallized from ethanol to give the titled compound (1.30 g,31%) as pale yellow crystals.

mp. 167.9-169.9° C.

IR(KBr): 1658, 1581, 1571, 1516, 1460, 1439, 1361, 1288, 1263, 1236,1155, 1122, 1095, 1062, 1032, 925, 736 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.64 (3H, s), 7.32 (1H, d, J=8.6 Hz), 7.54-7.72 (3H,m), 8.28-8.32 (1H, m), 8.54 (1H, d, J=7.6 Hz), 9.18 (1H, d, J=2.0 Hz).

Elemental Analysis for C₁₄H₁₀N₂OS₂

Calcd. C, 58.72; H, 3.52; N, 9.78.

Found C, 58.75; H, 3.81; N, 9.90.

Example 172

2-(1H-Indol-3-yl)-4H-1,3-benzothiazine-4-one

3-Cyanoindole (1.00 g, 7.0 mmol) and methyl thiosalicylate (1.20 g, 7.0mmol) were dissolved in toluene (10 ml), and triethylamine (1.5 ml, 10.4mmol) was added thereto. The reaction mixture was refluxed for 24 hrs.The solvent was evaporated. The residue was recrystallized from ethanolto give the titled compound (0.38 g, 20%) as pale yellow crystals.

mp. 276.5-277.0° C.

IR(KBr): 1626, 1591, 1516, 1493, 1454, 1439, 1356, 1329, 1300, 1261,1242, 1143, 1107, 1086, 1068, 908, 817, 729 cm⁻¹.

¹H-NMR (CDCl₃) δ: 7.28-7.31 (2H, m), 7.53-7.56 (1H, m), 7.61-7.66 (1H,m), 7.71-7.75 (2H, m), 8.31 (1H, d, J=7.6 Hz), 8.49-8.51 (1H, m), 8.55(1H, d, J=3.0 Hz), 12.41 (1H, br s).

Elemental Analysis for C₁₆H₁₀N₂OS

Calcd. C, 69.04; H, 3.62; N, 10.06.

Found C, 68.91; H, 3.78; N, 10.22.

Example 173

tert-Butyl 3-[6-(7-methoxy-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoate

2-Mercapto-4-methoxybenzoic acid (1.26 g, 6.8 mmol) and tert-butyl3-(6-cyano-2-pyridyl)propanoate (1.21 g, 5.2 mmol) were dissolved inpyridine (10 ml), and the reaction mixture was refluxed for 24 hrs. Thereaction mixture was concentrated under reduced pressure, subjected to asilica gel column chromatography, eluted with hexane-ethyl acetate (1:1,v/v) and recrystallized from ethyl acetate-hexane to give the titledcompound (0.96 g, 46%)

mp. 134.5-135.4° C.

IR (KBr): 2976, 1724, 1658, 1599, 1570, 1537, 1249, 1149, 1095 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 2.88 (2H, t, J=7.3 Hz), 3.19 (2H, t,J=7.3 Hz), 3.93 (3H, s), 7.03 (1H, d, J=2.4 Hz), 7.15 (1H, dd, J=2.4,8.8 Hz), 7.41 (1H, d, J=7.5 Hz), 7.79 (1H, dd, J=7.5, 7.5 Hz), 8.35 (1H,d, J=7.5 Hz), 8.47 (1H, d, J=8.8 Hz).

Elemental Analysis for C₂₁H₂₂N₂O₄S

Calcd. C, 63.30; H, 5.56; N, 7.03.

Found C, 63.28; H, 5.52; N, 7.01.

Example 174

3-[6-(7-Methoxy-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]p ropionicacid

A mixture of tert-butyl3-[6-(7-methoxy-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]_(p) ropanoate(0.40 g, 1.0 mmol) obtained in Example 173 and trifluoroacetic acid (5.0ml) was stirred at 0° C. for 2 hrs. The reaction mixture wasconcentrated under reduced pressure, combined with diisopropyl ether togive the crystals, which were collected by filtration and dried.

mp. 234.2-235.2° C.

IR (KBr): 3136, 1714, 1630, 1591, 1560, 1527, 1277, 1224 cm⁻¹.

¹H-NMR (DMSO-d₆) δ: 2.81 (2H, t, J=7.2 Hz), 3.13 (2H, t, J=7.2 Hz), 3.91(3H, s), 7.25 (1H, dd, J=2.5, 8.9 Hz), 7.48 (1H, d, J=2.5 Hz), 7.63 (1H,d, J=7.6 Hz), 7.99 (1H, dd, J=7.6, 7.6 Hz), 8.15 (1H, d, J=7.6 Hz), 8.26(1H, d, J=8.9 Hz), 12.00 (1H, br s).

Elemental Analysis for C₁₇H₁₄N₂O₄S 0.25H₂O

Calcd. C, 58.86; H, 4.21; N, 8.08.

Found C, 58.86; H, 4.27; N, 8.04.

Example 175

tert-Butyl 3-[6-(7-methyl-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoate

2-Mercapto-4-methylbenzoic acid (1.56 g, 9.3 mmol) and tert-butyl3-(6-cyano-2-pyridyl)propanoate (1.46 g, 6.3 mmol) were dissolved inpyridine (15 ml), and the mixture was refluxed for 6 hrs. The reactionmixture was concentrated under reduced pressure, subjected to silica gelcolumn chromatography, eluted with hexane-ethyl acetate (3:2, v/v) andrecrystallized from ethyl acetate-hexane to give the titled compound(1.29 g, 53%)

mp. 134.8-134.9° C.

IR (KBr): 2976, 2930, 1728, 1666, 1604, 1566, 1537, 1302, 1284, 1240,1149, 1099 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 2.49 (3H, s), 2.88 (2H, t, J=7.3 Hz),3.20 (2H, t, J=7.3 Hz), 7.40-7.43 3H, m), 7.79 (1H, m), 8.35 (1H, d,J=7.7 Hz), 8.43 (1H, d, J=8.6 Hz).

Elemental Analysis for C₂₁H₂₂N₂O₃S

Calcd. C, 65.95; H, 5.80; N, 7.32.

Found C, 65.91; H, 5.90; N, 7.25.

Example 176

3-[6-(7-Methyl-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]pr opionic acid

A mixture of tert-butyl3-[6-(7-methyl-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]pr opanoate(0.40 g, 1.0 mmol) obtained in Example 175 and trifluoroacetic acid (5.0ml) was stirred at 0° C. for 2 hrs. The reaction mixture wasconcentrated under reduced pressure and combined with diisopropyl etherto precipitate crystals, which were collected by filtration and dried togive the titled compound (0.33 g, 97%).

mp. 221.9-222.5° C.

IR (KBr): 3217, 1728, 1637, 1603, 1568, 1529, 1433, 1315, 1224, 1109,825, 779, 682 cm⁻¹.

¹H-NMR (DMSO-d₆) δ: 2.45 (3H, s), 2.81 (2H, t, J=7.1 Hz), 3.13 (2H, t,J=7.1 Hz), 7.52 (1H, d, J=8.2 Hz), 7.64 (1H, d, J=7.6 Hz), 7.71 (1H, s),7.99 (1H, dd, J=8.1, 8.2 Hz), 8.15 (1H, d, J=7.6 Hz), 8.23 (1H, d, J=8.1Hz), 12.00 (1H, br s).

Elemental Analysis for C₁₇H₁₄N₂O₃S

Calcd. C, 62.56; H, 4.32; N, 8.58.

Found C, 62.12; H, 4.10; N, 8.51.

Example 177

tert-Butyl 3-[6-(4-oxo-7-trifluoromethyl-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoate

2-Mercapto-4-trifluoromethylbenzoic acid (1.59 g, 7.2 mmol) andtert-butyl 3-(6-cyano-2-pyridyl)propanoate (1.32 g, 5.7 mmol) weredissolved in pyridine (15 ml), and the mixture was refluxed for 15 hrs.The reaction mixture was concentrated under reduced pressure, subjectedto a silica gel column chromatography, eluted with hexane-ethyl acetate(3:1, v/v) and recrystallized from ethyl acetate-hexane to give thetitled compound (0.85 g, 34%).

mp. 148.5-149.4° C.

IR (KBr): 2978, 1726, 1672, 1572, 1537, 1329, 1309, 1238, 1172, 1134,1084 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 2.88 (2H, t, J=7.2 Hz), 3.21 (2H, t,J=7.2 Hz), 7.46 (1H, d, J=7.6 Hz), 7.79-7.84 (2H, m), 7.90 (1H, s), 8.35(1H, d, J=7.6 Hz), 8.65 (1H, d, J=8.3 Hz).

Elemental Analysis for C₂₁H₁₉N₂O₃SF₃

Calcd. C, 57.79; H, 4.39; N, 6.42.

Found C, 57.89; H, 4.28; N, 6.56.

Example 178

3-[6-(4-Oxo-7-trifluoromethyl-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propionic acid

A mixture of tert-butyl3-[6-(4-oxo-7-trifluoromethyl-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoate (0.35 g, 0.8 mmol) and trifluoroacetic acid (5.0 ml)was stirred at 0° C. for 2 hrs. The reaction mixture was concentratedunder reduced pressure and combined with diisopropyl ether toprecipitate crystals, which were collected by filtration and dried togive the titled compound (0.27 g, 88%).

mp. 192.9-193.1° C.

IR (KBr): 3053, 2918, 1711, 1662, 1614, 1539, 1336, 1309, 1172, 1120,1086, 817 cm⁻¹.

¹H-NMR (DMSO-d₆) δ: 2.81 (2H, t, J=7.1 Hz), 3.14 (2H, t, J=7.1 Hz), 7.67(1H, d, J=7.4 Hz), 7.99-8.04 (2H, m), 8.18 (1H, d, J=7.4 Hz), 8.45-8.51(2H, m), 12.00 (1H, br s).

Elemental Analysis for C₁₇H₁₁N₂O₃SF₃·0.75H₂O

Calcd. C, 51.84; H, 3.20; N, 7.11.

Found C, 51.99; H, 2.92; N, 7.00.

Example 179

tert-Butyl 3-[6-(7-chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoate

tert-Butyl 3-(6-cyano-2-pyridyl)propanoate (1.6 g, 6.9 mmol) and4-chlorothiosalicylic acid (2.6 g, 13.7 mmol) were dissolved in pyridine(15 ml), and the mixture was refluxed for 13 hrs. The solvent wasevaporated. The residue was subjected to a silica gel columnchromatography. The fractions eluted with hexane-ethyl acetate (3:1,v/v) were collected, concentrated and recrystallized from hexane-ethylacetate to give the titled compound (1.4 g, 51%) as pale yellowcrystals.

mp. 167.9-168.2° C.

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 2.87 (2H, t, J=7.2 Hz), 3.20 (2H, t,J=7.2 Hz), 7.43 (1H, d, J=7.3 Hz), 7.56 (1H, dd, J=2.0, 8.5 Hz), 7.62(1H, d, J=2.0 Hz), 7.80 (1H, dd, J=7.3, 7.5 Hz), 8.34 (1H, d, J=7.5 Hz),8.47 (1H, d, J=8.5 Hz).

IR(KBr): 2976, 2932, 1726, 1678, 1585, 1570, 1535, 1379, 1271, 1149,1093 cm⁻¹.

Elemental Analysis for C₂₀H₁₉N₂O₃SCl

Calcd. C, 59.62; H, 4.75; N, 6.95.

Found C, 59.65; H, 4.96; N, 7.15.

Example 180

3-[6-(7-Chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]pr opionic acid

tert-Butyl 3-[6-(7-chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoate (0.60 g, 1.5 mmol) was dissolved in trifluoroacetic acid (5ml), and the mixture was stirred at 0° C. for 2 hrs. The solvent wasevaporated and the residue was crystallized from diisopropyl ether togive the titled compound (0.49 g, 96%) as white crystals.

mp. 224.4-224.7° C.

¹H-NMR (DMSO-d₆) δ: 2.80 (2H, t, J=7.1 Hz), 3.13 (2H, t, J=7.1 Hz), 7.65(1H, d, J=7.7 Hz), 7.73 (1H, dd, J=2.0, 8.5 Hz), 8.00 (1H, m), 8.13-8.17(2H, m), 8.31 (1H, d, J=8.5 Hz), 12.20 (1H, br s).

IR(KBr): 3051, 2922, 1709, 1664, 1585, 1566, 1529, 1379, 1261, 1230,1095 cm⁻¹.

Elemental Analysis for C₁₆H₁₁N₂O₃SCl·0.25H₂O

Calcd. C, 54.71; H, 3.30; N, 7.97.

Found C, 54.85; H, 3.14; N, 7.82.

Reference Example 48

Methyl 2-[[(dimethylamino)carbothioyl]oxy]-4-fluorobenzoate

4-Fluorosalicylic acid (10.0 g, 64 mmol) was dissolved in methanol (300ml), and concentrated sulfuric acid (6.3 g, 64 mmol) was added thereto.The reaction mixture was refluxed for 48 hrs. The solvent wasevaporated, and the residue was neutralized with 2 N aqueous sodiumhydroxide solution. Ethyl acetate was added to the mixture. The organiclayer was washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated to give methyl 4-fluorosalicylate(10.0 g, 92%) as white crystals. Methyl 4-fluorosalicylate (10.0 g, 58mmol) and N,N-dimethylthiocarbamoyl chloride (9.6 g, 77 mmol) weredissolved in DMF (100 ml), and 1,4-diazabicyclo[2.2.2]octane (8.5 g, 75mmol) was added thereto. The reaction mixture was stirred at roomtemperature for 7 hrs. The reaction mixture was combined with ethylacetate and water. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated. Theresidue was subjected to a silica gel column chromatography. Thefractions eluted with ethylacetate-hexane (1:5, v/v) were collected,concentrated and recrystallized from ethyl acetate-hexane to give thetitled compound (12.1 g, 80%) as white crystals.

mp. 106.8-107.2° C.

¹H-NMR (CDCl₃) δ: 3.39 (3H, s), 3.46 (3H, s), 3.83 (3H, s), 6.87 (1H,m), 7.02 (1H, m), 8.03 (1H, m).

IR(KBr): 2949, 1728, 1606, 1539, 1496, 1396, 1286, 1257, 1151, 1113,1086 cm⁻¹.

Elemental Analysis for C₁₁H₁₂NO₃SF

Calcd. C, 51.35; H, 4.70; N, 5.44.

Found C, 51.47; H, 4.93; N, 5.41.

Reference Example 49

Methyl 2-[[(dimethylamino)carbonyl]thio]-4-fluorobenzoate

Methyl 2-[[(dimethylamino)carbothioyl]oxy]-4-fluorobenzoate (4.7 g, 18mmol) was melted at 190° C. and stirred at the same temperature for 18hrs. The mixture was subjected to a silica gel column chromatography.The fractions eluted with ethylacetate-hexane (1:3, v/v) were collectedand concentrated to give the titled compound (4.3 g, 91%).

¹H-NMR (CDCl₃) δ: 3.05 (3H, s), 3.10 (3H, s), 3.87 (3H, s), 7.10 (1H,m), 7.38 (1H, dd, J=2.6, 8.8 Hz), 7.94 (1H, dd, J=5.8, 8.8 Hz).

Reference Example 50

4-Fluorothisalicylic acid

A mixture of methyl 2-[[(dimethylamino)carbonyl] thio]-4-fluorobenzoate(4.7 g, 18 mmol) and 10% aqueous sodium hydroxide solution (36 g, 90mmol) was stirred at 100° C. for 14 hrs. The reaction mixture wasacidified (pH 3) by the addition of 6 N hydrochloric acid, and theprecipitates were collected. The precipitates were dissolved in ethylacetate, dried over anhydrous magnesium sulfate. The solvent wasevaporated to give the titled compound (2.7 g, 87%) as pale yellowcrystals.

¹H-NMR (CDCl₃+DMSO-d₆) δ: 5.50 (1H, br s), 6.83 (1H, m), 7.02 (1H, dd,J=2.5, 9.3 Hz), 8.10 (1H, m).

Example 181

tert-Butyl 3-[6-(7-fluoro-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoate

tert-Butyl 3-(6-cyano-2-pyridyl)propanoate (1.5 g, 6.5 mmol) and4-fluorothiosalicylic acid (1.7 g, 9.7 mmol) were dissolved in pyridine(10 ml), and the mixture was refluxed for 15 hrs. The solvent wasevaporated, and the residue was subjected to a silica gel columnchromatography. The fractions eluted with hexane-ethyl acetate (3:1,v/v) were collected, concentrated and recrystallized from hexane-ethylacetate to give the titled compound (1.36 g, 54%) as white crystals.

mp. 158.5-159.5° C.

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 2.87 (2H, t, J=7.2 Hz), 3.20 (2H, t,J=7.2 Hz), 7.29-7.34 (2H, m), 7.43 (1H, d, J=7.6 Hz), 7.81 (1H, m), 8.34(1H, d, J=7.6 Hz), 8.58 (1H, dd, J=5.8, 9.5 Hz).

IR(KBr): 3061, 2976, 2930, 1730, 1672, 1599, 1581, 1547, 1240, 1151cm⁻¹.

Elemental Analysis for C₂₀H₁₉N₂O₃SF

Calcd. C, 62.16; H, 4.96; N, 7.25.

Found C, 62.05; H, 4.95; N, 7.15.

Example 182

3-[6-(7-Fluoro-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]pr opionic acid

tert-Butyl 3-[6-(7-fluoro-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoate (0.50 g, 1.3 mmol) was dissolved in trifluoroacetic acid (5ml), and the mixture was stirred at 0° C. for 2 hrs. The solvent wasevaporated, and the residue was crystallized from diethyl ether to givethe titled compound (0.43 g, 99%) as white crystals.

mp. 215.0-217.0° C.

¹H-NMR (DMSO-d₆) δ: 2.81 (2H, t, J=7.2 Hz), 3.13 (2H, t, J=7.2 Hz), 7.56(1H, m), 7.66 (1H, d, J=7.7 Hz), 7.92 (1H, m), 8.01 (1H, m), 8.17 (1H,d, J=7.7 Hz), 8.40 (1H, m), 12.22 (1H, s).

IR(KBr): 3136, 1714, 1630, 1591, 1560, 1527, 1277, 1224 cm⁻¹.

Elemental Analysis for C₁₆H₁₁N₂O₃SF 0.25H₂O

Calcd. C, 57.39; H, 3.46; N, 8.37.

Found C, 57.04; H, 3.12; N, 8.13.

Example 183

tert-Butyl 3-[2-(7-chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate

4-Chlorothiosalicylic acid (2.3 g, 12.2 mmol) and tert-butyl3-(2-cyano-4-pyridyl)propanoate (1.4 g, 6.0 mmol) were dissolved inpyridine (20 ml), and the mixture was refluxed for 16 hrs. The solventwas evaporated and the residue was subjected to a silica gel columnchromatography. The fraction eluted with hexane-ethyl acetate (2:1, v/v)were collected, concentrated and recrystallized fromhexane-tetrahydrofuran to give the titled compound (1.3 g, 52%) as whitecrystals.

mp. 151.8-152.1° C.

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 2.64 (2H, t, J=7.4 Hz), 3.02 (2H, t,J=7.4 Hz), 7.42 (1H, dd, J=1.5, 4.8 Hz), 7.56-7.60 (2H, m), 8.40 (1H,s), 8.48 (1H, d, J=8.2 Hz), 8.62 (1H, d, J=4.8 Hz).

IR(KBr): 2976, 1726, 1666, 1585, 1566, 1537, 1278, 1151, 1093 cm⁻¹.

Elemental Analysis for C₂₀H₁₉N₂O₃SCl

Calcd. C, 59.62; H, 4.75; N, 6.95.

Found C, 59.54; H, 4.45; N, 6.97.

Example 184

tert-Butyl 3-[2-(7-fluoro-4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate

4-Fluorothiosalicylic acid (1.9 g, 11.3 mmol) and tert-butyl3-(2-cyano-4-pyridyl)propanoate (1.3 g, 5.6 mmol) were dissolved inpyridine (20 ml), and the mixture was refluxed for 18 hrs. The solventwas evaporated, and the residue was subjected to a silica gel columnchromatography. The fractions eluted with hexane-ethyl acetate (2:1,v/v) were collected, concentrated and recrystallized fromhexane-tetrahydrofuran to give the titled compound (1.2 g, 54%) as whitecrystals.

mp. 137.6-138.1° C.

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 2.64 (2H, t, J=7.5 Hz), 3.02 (2H, t,J=7.5 Hz), 7.29-7.35 (2H, m), 7.42 (1H, dd, J=1.2, 4.8 Hz), 8.40 (1H,s), 8.58 (1H, m), 8.62 (1H, d, J=5.0 Hz).

IR(KBr): 2978, 2932, 1726, 1666, 1601, 1577, 1541, 1477, 1277, 1240,1151 cm⁻¹.

Elemental Analysis for C₂₀H₁₉N₂O₃SF

Calcd. C, 62.16; H, 4.96; N, 7.25.

Found C, 62.29; H, 5.15; N, 7.31.

Example 185

3-[2-(7-Chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]pr opionic acid

tert-Butyl 3-[2-(7-chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate (1.00 g, 2.4 mmol) was dissolved in trifluoroacetic acid (10ml), and the mixture was stirred at 0° C. for 2 hrs. The solvent wasevaporated, and the residue was recrystallized fromhexane-tetrahydrofuran-methanol to give the titled compound (0.66 g,76%) as white crystals.

mp. 262.9-263.5° C.

¹H-NMR (DMSO-d₆) δ: 2.68 (2H, t, J=7.0 Hz), 3.00 (2H, t, J=7.0 Hz), 7.64(1H, s), 7.73 (1H, m), 8.11 (1H, m), 8.21 (1H, m), 8.30 (1H, m), 8.68(1H, m), 12.26 (1H, s).

IR(KBr): 3065, 1718, 1626, 1560, 1525, 1388, 1302, 1184, 1101 cm⁻¹.

Elemental Analysis for C₁₆H₁₁N₂O₃SCl

Calcd. C, 55.41; H, 3.20; N, 8.08.

Found C, 55.28; H, 3.07; N, 8.01.

Example 186

3-[2-(7-Fluoro-4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]pr opionic acid

tert-Butyl 3-[2-(7-fluoro-4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate (0.92 g, 2.3 mmol) was dissolved in trifluoroacetic acid (10ml), and the mixture was stirred at 0° C. for 2 hrs. The solvent wasevaporated, and the residue was recrystallized from diisopropylether-methanol to give the titled compound (0.56 g, 71%) as whitecrystals.

mp. 240.0° C. (decomposed)

¹H-NMR (DMSO-d₆) δ: 2.69 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 7.57(1H, m), 7.65 (1H, m), 7.91 (1H, m), 8.22 (1H, s), 8.39 (1H, m), 8.68(1H, m), 12.26 (1H, s).

IR(KBr): 2930, 1720, 1630, 1601, 1576, 1537, 1475, 1292, 1224, 1192,1097 cm⁻¹.

Elemental Analysis for C₁₆H₁₁N₂O₃SF

Calcd. C, 58.17; H, 3.36; N, 8.48.

Found C, 58.22; H, 3.30; N, 8.46.

Reference Example 51

4-Bromosalicylic acid

4-Aminosalicylic acid (15.0 g, 98 mmol) and hydrobromic acid (47%, 100ml) were mixed with water (100 ml). A solution of sodium nitrite (6.8 g,98 mmol) in water (50 ml) was added dropwise to the mixture at 0° C.,and the mixture was stirred at the same temperature for 30 minutes. Amixture of cuprous bromide (16.9 g, 117 mmol) and hydrobromic acid (47%,45 ml) was added dropwise to the mixture at 0° C., and the mixture wasstirred at the same temperature for 1 hr. The reaction mixture wascombined with ethyl acetate and extracted. The organic layer was washedwith saturated brine and dried over anhydrous magnesium sulfate. Thesolvent was evaporated to give the titled compound (15.5 g, 73%) as agray solid.

¹H-NMR (DMSO-d₆) δ: 7.09 (1H, dd, J=0.9, 8.4 Hz), 7.19 (1H, d, J=0.9Hz), 7.69 (1H, d, J=8.4 Hz), 10.33 (1H, br s).

Reference Example 52

Methyl 4-bromo-2-[[(dimethylamino)carbothioyl]oxy]benzoate

4-Bromosalicylic acid (15.5 g, 71 mmol) was dissolved in methanol (500ml), and concentrated sulfuric acid (9.7 g, 99 mmol) was added thereto.The reaction mixture was refluxed for 24 hrs, and the solvent wasevaporated. The residue was neutralized with 2 N aqueous sodiumhydroxide solution and extracted with ethyl acetate. The organic layerwas washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated. The residue was subjected to asilica gel column chromatography. The fractions eluted with ethylacetate-hexane (1:20, v/v) were collected and concentrated to givemethyl 4-bromosalicylate (8.7 g, 52%). Methyl 4-bromosalicylate (8.7 g,37 mmol) and N,N-dimethylthiocarbamoyl chloride (6.0 g, 48 mmol) weredissolved in DMF (80 ml), and 1,4-diazabicyclo[2.2.2]octane (5.5 g, 49mmol) was added thereto. The reaction mixture was stirred at roomtemperature for 24 hrs. The reaction mixture was combined with ethylacetate and water. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated, andthe residue was subjected to a silica gel column chromatography. Thefractions eluted with ethyl acetate-hexane (1:4, v/v) were collected,concentrated and recrystallized from ethyl acetate-hexane to give thetitled compound (10.6 g, 88%) as white crystals.

mp. 117.5-118.3° C.

¹H-NMR (CDCl₃) δ: 3.38 (3H, s), 3.45 (3H, s), 3.83 (3H, s), 7.31 (1H, d,J=1.9 Hz), 7.45 (1H, dd, J=1.9, 8.4 Hz), 7.86 (1H, d, J=8.4 Hz).

IR(KBr): 2947, 1712, 1595, 1550, 1394, 1286, 1207, 1116 cm⁻¹.

Elemental Analysis for C₁₁H₁₂NO₃SBr

Calcd. C, 41.52; H, 3.80; N, 4.40.

Found C, 41.65; H, 3.71; N, 4.39.

Reference Example 53

Methyl 4-bromo-2-[[(dimethylamino)carbonyl]thio]benzoate

Methyl 4-bromo-2-[[(dimethylamino)carbothioyl]oxy]benzoate (5.4 g, 17mmol) was melted with heating at 190° C. and stirred at the sametemperature for 6 hrs. The mixture was subjected to a silica gel columnchromatography. The fractions eluted with ethyl acetate-hexane (1:2,v/v) were collected and concentrated to give the titled compound (3.2 g,59%).

¹H-NMR (CDCl₃) δ: 3.04 (3H, br s), 3.11 (3H, br s), 3.87 (3H, s), 7.55(1H, dd, J=2.0, 8.4 Hz), 7.78 (1H, d, J=8.4 Hz), 7.79 (1H, d, J=2.0 Hz).

Reference Example 54

4-Bromothiosalicylic acid

A mixture of methyl 4-bromo-2-[[(dimethylamino)carbonyl]thio]benzoate(3.2 g, 10 mmol) and 10% aqueous sodium hydroxide solution (20 g, 50mmol) was stirred at 100° C. for 14 hrs. The reaction mixture wasacidified (pH 3) by the addition of 6 N hydrochloric acid. Theprecipitates were collected by filtration, dissolved in ethyl acetateand dried over anhydrous magnesium sulfate. The solvent was evaporatedto give the titled compound (2.3 g, 100%) as white crystals.

¹H-NMR (DMSO-d₆) δ: 7.37 (1H, dd, J=1.8, 8.5 Hz), 7.80-7.85 (2H, m).

Example 187

tert-Butyl 3-[2-(7-bromo-4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate

tert-Butyl 3-(2-cyano-4-pyridyl)propanoate (1.3 g, 5.6 mmol) and4-bromothiosalicylic acid (1.8 g, 8.0 mmol) were dissolved in pyridine(20 ml), and the mixture was refluxed for 18 hrs. The solvent wasevaporated, and the residue was subjected to a silica gel columnchromatography. The fractions eluted with hexane-ethyl acetate (3:2,v/v) were collected, concentrated and recrystallized fromhexane-tetrahydrofuran to give the titled compound (0.63 g, 25%) aswhite crystals.

mp. 172.9-173.7° C.

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 2.64 (2H, t, J=7.5 Hz), 3.02 (2H, t,J=7.5 Hz), 7.42 (1H, d, J=4.9 Hz), 7.71-7.76 (2H, m), 8.38-8.40 (2H, m),8.62 (1H, d, J=4.9 Hz)

IR(KBr): 2978, 2932, 1726, 1660, 1579, 1562, 1529, 1367, 1278, 1157cm⁻¹.

Elemental Analysis for C₂₀H₁₉N₂O₃SBr

Calcd. C, 53.70; H, 4.28; N, 6.26.

Found C, 53.86; H, 4.05; N, 6.28.

Example 188

3-[2-(7-Bromo-4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]pro pionic acid

tert-Butyl 3-[2-(7-bromo-4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate (0.49 g, 1.1 mmol) was dissolved in trifluoroacetic acid (5 ml),and the mixture was stirred at 0° C. for 2 hrs. The solvent wasevaporated, and the residue was recrystallized from diisopropylether-tetrahydrofuran to give the titled compound (0.38 g, 89%) as whitecrystals.

mp. 257.5-259.1° C.

¹H-NMR (DMSO-d₆) δ: 2.68 (2H, t, J=7.3 Hz), 3.00 (2H, t, J=7.3 Hz), 7.65(1H, d, J=4.9 Hz), 7.87 (1H, m), 8.21-8.27 (3H, m), 8.69 (1H, d, J=4.9Hz), 12.23 (1H, br s).

IR(KBr): 3059, 1718, 1626, 1577, 1560, 1523, 1385, 1302, 1184 cm⁻¹.

Elemental Analysis for C₁₆H₁₁N₂O₃SBr

Calcd. C, 49.12; H, 2.83; N, 7.16.

Found C, 49.40; H, 2.83; N, 7.21.

Reference Example 55

4-Methyl-2-pyridinecarbaldehyde

Diisobutyl aluminium hydride in toluene (1.5 M, 43.5 ml, 65 mmol) wasadded dropwise to a solution of 2-cyano-4-methylpyridine (7.0 g, 59mmol) in dichloromethane (180 ml) at −78° C., and the mixture wasstirred at the same temperature for 2 hrs. The reaction mixture wascombined with concentrated hydrochloric acid (28 ml) and water (112 ml),and the water layer and the organic layer were separated. The organiclayer was extracted with 2 N hydrochloric acid. The water layer wascombined, neutralized with sodium hydrogen carbonate and extracted withdiethyl ether. The extract was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated to give thetitled compound (2.7 g, 37%).

Reference Example 56

tert-Butyl (E)-3-(4-methyl-2-pyridyl)-2-propenoate

A solution of tert-butyl diethylphosphonoacetate (6.2 g, 24 mmol) intetrahydrofuran (20 ml) was added dropwise to a mixture of sodiumhydride (60% in oil, 1.1 g, 26 mmol) and tetrahydrofuran (120 ml) at 0°C., and the mixture was stirred at the same temperature for 30 minutes.Successively, a solution of 4-methyl-2-pyridinecarbaldehyde (1.5 g, 12mmol) in tetrahydrofuran (30 ml) was added dropwise to the mixture at 0°C., and the mixture was stirred at room temperature for 1 hr. Thereaction mixture was combined with water and extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated. Theresidue was subjected to a silica gel column chromatography. Thefractions eluted with ethylacetate-hexane (1:5, v/v) were collected andconcentrated to give the titled compound (1.9 g, 70%).

¹H-NMR (CDCl₃) δ: 1.52 (9H, s), 2.36 (3H, s), 6.80 (1H, d, J=15.7 Hz),7.07 (1H, d, J=4.8 Hz), 7.24 (1H, s), 7.55 (1H, d, J=15.7 Hz), 8.48 (1H,d, J=4.8 Hz).

Reference Example 57

tert-Butyl 3-(4-methyl-2-pyridyl)propanoate

tert-Butyl (E)-3-(4-methyl-2-pyridyl)-2-propenoate (1.9 g, 8.5 mmol) wasdissolved in methanol (80 ml), and 10% palladium-carbon (200 mg) wasadded thereto. The mixture was stirred under hydrogen atmosphere at roomtemperature for 3 hrs. Palladium-carbon was filtered off, and thefiltrate was concentrated to give the titled compound (1.8 g, 90%).

¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 2.31 (3H, s), 2.68 (2H, t, J=7.6 Hz),3.02 (2H, t, J=7.6 Hz), 6.93 (1H, d, J=4.8 Hz), 6.99 (1H, s), 8.36 (1H,d, J=4.8 Hz).

Reference Example 58

tert-Butyl 3-(4-methyl-2-pyridyl)propanoate N-oxide

tert-Butyl 3-(4-methyl-2-pyridyl)propanoate (1.8 g, 8.3 mmol) and3-chloroperbenzoic acid (ca. 77%, 2.4 g, 10.8 mmol) were dissolved inethyl acetate (50 ml), and the mixture was stirred at room temperaturefor 4 hrs. The solvent was evaporated, and the residue was subjected toa silica gel column chromatography. The fractions eluted withmethanol-ethyl acetate (1:4, v/v) were collected and concentrated togive the titled compound (1.7 g, 88%).

¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 2.31 (3H, s), 2.75 (2H, t, J=7.1 Hz),3.14 (2H, t, J=7.1 Hz), 6.95 (1H, dd, J=2.3, 6.6 Hz), 7.10 (1H, d, J=2.3Hz), 8.13 (1H, d, J=6.6 Hz).

Reference Example 59

tert-Butyl 3-(6-cyano-4-methyl-2-pyridyl)propanoate

tert-Butyl 3-(4-methyl-2-pyridyl)propanoate N-oxide (1.7 g, 7.3 mmol)was dissolved in nitroethane (40 ml), and trimethylsilyl cyanide (1.4 g,14.7 mmol) and N,N-dimethylcarbamoyl chloride (1.2 g, 11.3 mmol) wereadded thereto. The mixture was stirred at room temperature for 22 hrs.The solvent was evaporated, and the residue was subjected to a silicagel column chromatography. The fractions eluted with ethylacetate-hexane (1:4, v/v) were collected and concentrated to give thetitled compound (1.4 g, 79%).

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 2.37 (3H, s), 2.71 (2H, t, J=7.1 Hz),3.05 (2H, t, J=7.1 Hz), 7.21 (1H, s), 7.34 (1H, s)

IR(KBr): 2978, 2932, 2233, 1726, 1604, 1367, 1151 cm⁻¹.

Example 189

tert-Butyl 3-[4-methyl-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoate

tert-Butyl 3-(6-cyano-4-methyl-2-pyridyl)propanoate (0.72 g, 2.9 mmol)and methyl thiosalicylate (0.99 g, 5.9 mmol) were dissolved in toluene(4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. Themixture was refluxed for 14 hrs. The solvent was evaporated, and theresidue was subjected to a silica gel column chromatography. Thefractions eluted with ethyl acetate-hexane (1:2, v/v) were collected,concentrated and recrystallized from ethyl acetate-hexane to give thetitled compound (0.61 g, 54%) as white crystals.

mp. 168.5-169.3° C.

¹H-NMR (CDCl₃) δ: 1.43 (9H, s), 2.42 (3H, s), 2.86 (2H, t, J=7.2 Hz),3.14 (2H, t, J=7.2 Hz), 7.23 (1H, s), 7.60-7.68 (3H, m), 8.22 (1H, s),8.55 (1H, m)

IR(KBr): 2976, 2928, 1726, 1655, 1572, 1531, 1365, 1298, 1153, 1095, 758cm⁻¹.

Elemental Analysis for C₂₁H₂₂N₂O₃S

Calcd. C, 65.95; H, 5.80; N, 7.32.

Found C, 66.01; H, 5.75; N, 7.32.

Example 190

tert-Butyl 3-[6-(7-chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-4-methyl-2-pyridyl]propanoate

tert-Butyl 3-(6-cyano-4-methyl-2-pyridyl)propanoate (0.69 g, 2.8 mmol)and 4-chlorothiosalicylic acid (1.05 g, 5.7 mmol) were dissolved inpyridine (10 ml). The mixture was refluxed for 22 hrs. The solvent wasevaporated, and the residue was subjected to a silica gel columnchromatography. The fractions eluted with hexane-ethyl acetate (3:1,v/v) were collected, concentrated and recrystallized from hexane-ethylacetate to give the titled compound (0.33 g, 28%) as white crystals.

mp. 162.3-163.0° C.

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 2.42 (3H, s), 2.85 (2H, t, J=7.2 Hz),3.14 (2H, t, J=7.2 Hz), 7.24 (1H, s), 7.55 (1H, dd, J=1.9, 8.5 Hz), 7.61(1H, d, J=1.9 Hz), 8.20 (1H, s), 8.47 (1H, d, J=8.5 Hz).

IR(KBr): 2976, 2930, 1724, 1666, 1585, 1566, 1537, 1282, 1153, 1093cm⁻¹.

Elemental Analysis for C₂₁H₂₁N₂O₃SCl

Calcd. C, 60.50; H, 5.08; N, 6.72.

Found C, 60.64; H, 5.02; N, 6.65.

Example 191

3-[4-Methyl-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]pr opionic acid

tert-Butyl 3-[4-methyl-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoate (0.44 g, 1.1 mmol) was dissolved in trifluoroacetic acid (5ml), and the mixture was stirred at 0° C. for 2 hrs. The solvent wasevaporated, and the residue was recrystallized from diisopropylether-methanol to give the titled compound (0.33 g, 87%) as whitecrystals.

mp. 244.6-245.5° C.

¹H-NMR (DMSO-d₆) δ: 2.44 (3H, s), 2.79 (2H, t, J=7.1 Hz), 3.07 (2H, t,J=7.1 Hz), 7.48 (1H, s), 7.71 (1H, m), 7.83 (1H, m), 7.92 (1H, d, J=7.8Hz), 8.03 (1H, s), 8.34 (1H, dd, J=1.0, 7.8 Hz), 12.19 (1H, s).

IR(KBr): 3223, 1728, 1637, 1570, 1527, 1440, 1307, 1224, 835, 752 cm⁻¹.

Elemental Analysis for C₁₇H₁₄N₂O₃S

Calcd. C, 62.56; H, 4.32; N, 8.58.

Found C, 62.48; H, 4.32; N, 8.50.

Example 192

3-[6-(7-Chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-4-methyl-2-pyridyl]propionic acid

tert-Butyl 3-[6-(7-chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-4-methyl-2-pyridyl]propanoate (0.25 g, 0.61 mmol) was dissolved in trifluoroaceticacid (5 ml), and the mixture was stirred at 0° C. for 2 hrs. The solventwas evaporated, and the residue was recrystallized fromhexane-tetrahydrofuran to give the titled compound (0.16 g, 74%) aswhite crystals.

mp. 232.2-233.2° C.

¹H-NMR (DMSO-d₆) δ: 2.43 (3H, s), 2.78 (2H, t, J=7.2 Hz), 3.07 (2H, t,J=7.2 Hz), 7.48 (1H, s), 7.73 (1H, dd, J=2.0, 8.5 Hz), 8.01 (1H, s),8.13 (1H, d, J=2.0 Hz), 8.30 (1H, d, J=8.5 Hz), 12.17 (1H, s).

IR(KBr): 2922, 1695, 1655, 1560, 1535, 1381, 1309, 1095 cm⁻¹.

Elemental Analysis for C₁₇H₁₃N₂O₃SCl

Calcd. C, 56.59; H, 3.63; N, 7.76.

Found C, 56.41; H, 3.37; N, 7.74.

Reference Example 60

6-(2-Thienyl)-2-pyridinecarbonitrile

6-Chloro-2-pyridinecarbonitrile (1.2 g, 8.6 mmol) and 2-thiopheneboricacid (1.9 g, 15.3 mmol) were dissolved in toluene (100 ml)-ethanol (25ml), and potassium carbonate (3.0 g, 21.7 mmol) and water (25 ml) wereadded thereto. The mixture was deairated under reduced pressure for 10minutes. Tetrakis(triphenylphosphine)palladium (0) (0.5 g, 0.43 mmol)was added to the reaction mixture under argon atmosphere, and themixture was refluxed for 16 hrs. The reaction mixture was combined withethyl acetate and water. The organic layer was separated, washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated, and the residue was subjected to a silica gel columnchromatography. The fractions eluted with hexane-ethyl acetate (4:1,v/v) were collected, concentrated and recrystallized from hexane-ethylacetate to give the titled compound (1.3 g, 85%)

mp. 88.2-88.6° C.

¹H-NMR (CDCl₃) δ: 7.13 (1H, dd, J=3.7, 5.0 Hz), 7.47 (1H, dd, J=0.9, 5.0Hz), 7.52 (1H, m), 7.66 (1H, dd, J=1.0, 3.7 Hz), 7.76-7.83 (2H, m)

IR(KBr): 3105, 3061, 2235, 1585, 1452, 1423, 860 cm⁻¹.

Elemental Analysis for C₁₀H₆N₂S

Calcd. C, 64.49; H, 3.25; N, 15.04.

Found C, 64.44; H, 3.14; N, 15.08.

Reference Example 61

6-(2-Furyl)-2-pyridinecarbonitrile

6-Chloro-2-pyridinecarbonitrile (0.90 g, 6.5 mmol) and 2-furanboric acid(1.1 g, 9.8 mmol) were dissolved in toluene (80 ml)-ethanol (205 ml),and potassium carbonate (2.2 g, 15.9 mmol) and water (20 ml) were addedthereto. The mixture was deairated under reduced pressure for 10minutes. Tetrakis(triphenylphosphine)palladium (0) (0.36 g, 0.31 mmol)was added to the reaction mixture under argon atmosphere, and themixture was refluxed for 13 hrs. The reaction mixture was combined withethyl acetate and water. The organic layer was separated, washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated, and the residue was subjected to a silica gel columnchromatography. The fractions eluted with hexane-ethyl acetate (5:1,v/v) were collected, concentrated and recrystallized from hexane-ethylacetate to give the titled compound (0.97 g, 87%).

mp. 90.2-90.3° C.

¹H-NMR (CDCl₃) δ: 6.57 (1H, dd, J=1.6, 3.5 Hz), 7.20 (1H, m), 7.51 (1H,dd, J=1.6, 6.9 Hz), 7.56 (1H, dd, J=0.6, 1.6 Hz), 7.80-7.89 (2H, m).

IR(KBr): 3155, 3057, 2237, 1604, 1574, 1491, 1440, 1168, 1006, 922, 804cm⁻¹.

Elemental Analysis for C₁₀H₆N₂O

Calcd. C, 70.58; H, 3.55; N, 16.46.

Found C, 70.63; H, 3.48; N, 16.66.

Example 193

2-[6-(2-Thienyl)-2-pyridyl]-4H-1,3-benzothiazin-4-one

6-(2-Thienyl)-2-pyridinecarbonitrile (0.56 g, 3.0 mmol) and methylthiosalicylate (0.77 g, 4.6 mmol) were dissolved in toluene (4 ml), andtriethylamine (2.0 ml, 14.3 mmol) was added thereto. The reactionmixture was refluxed for 10 hrs. After cooling, the precipitates werecollected by filtration and recrystallized from tetrahydrofuran-hexaneto give the titled compound (0.84 g, 86%) as pale yellow crystals.

mp. 222.2-223.4° C.

¹H-NMR (CDCl₃) δ: 7.16 (1H, m), 7.48 (1H, d, J=5.1 Hz), 7.62-7.71 (4H,m), 7.81-7.90 (2H, m), 8.35 (1H, t, J=7.2 Hz), 8.55 (1H, d, J=7.6 Hz).

IR(KBr): 3065, 1655, 1572, 1535, 1454, 1302, 1278, 1238, 1099, 806 cm⁻¹.

Elemental Analysis for C₁₇H₁₀N₂OS₂

Calcd. C, 63.33; H, 3.13; N, 8.69.

Found C, 63.38; H, 3.32; N, 8.87.

Example 194

2-[6-(2-Furyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one

6-(2-Furyl)-2-pyridinecarbonitrile (0.60 g, 3.5 mmol) and methylthiosalicylate (1.01 g, 6.0 mmol) were dissolved in toluene (4 ml), andtriethylamine (2.0 ml, 14.3 mmol) was added thereto. The reactionmixture was refluxed for 12 hrs. After cooling, the precipitates werecollected by filtration and recrystallized from tetrahydrofuran-hexaneto give the titled compound (0.75 g, 69%) as pale yellow crystals.

mp. 217.9-218.4° C.

¹H-NMR (CDCl₃) δ: 6.60 (1H, dd, J=1.7, 3.4 Hz), 7.27 (1H, d, J=3.4 Hz),7.59-7.72 (4H, m), 7.86-7.94 (2H, m), 8.36 (1H, m), 8.55 (1H, m).

IR(KBr): 3123, 1666, 1574, 1537, 1493, 1440, 1300, 1236, 1095, 908 cm⁻¹.

Elemental Analysis for C₁₇H₁₀N₂O₂S 0.25H₂O

Calcd. C, 65.69; H, 3.40; N, 9.01.

Found C, 65.94; H, 3.26; N, 9.18.

Reference Example 62

2-(1,3-Oxazol-5-yl)pyridine

Picolinaldehyde (2.5 g, 23 mmol) and toluenesulfonylmethyl isocyanide(5.3 g, 27 mmol) were dissolved in methanol (30 ml), and potassiumcarbonate (3.5 g, 25 mmol) was added thereto. The mixture was refluxedfor 30 minutes. The solvent was evaporated, and ethyl acetate and waterwere added to the residue. The organic layer was washed with saturatedbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated. The residue was subjected to a silica gel columnchromatography. The fractions eluted with hexane-ethyl acetate (2:3,v/v) were collected and concentrated to give the titled compound.

¹H-NMR (CDCl₃) δ: 7.25 (1H, m), 7.66-7.80 (3H, m), 7.97 (1H, s), 8.65(1H, m).

Reference Example 63

2-(1,3-Oxazol-5-yl)pyridine N-oxide

2-(1,3-Oxazol-5-yl)pyridine (2.8 g, 19 mmol) and 3-chloroperbenzoic acid(77%, 13.6 g, 58 mmol) were dissolved in ethyl acetate, and the mixturewas stirred at room temperature for 6 days. The solvent was evaporated,and the residue was subjected to a silica gel column chromatography. Thefractions eluted with methanol-ethyl acetate (1:4, v/v) were collectedand concentrated to give the titled compound (1.1 g, 34%).

¹H-NMR (CDCl₃) δ: 7.22 (1H, m), 7.36 (1H, m), 7.87 (1H, dd, J=1.9, 8.1Hz), 8.04 (1H, s), 8.33 (1H, d, J=6.4 Hz), 8.54 (1H, s).

Reference Example 64

6-(1,3-Oxazol-5-yl)-2-pyridinecarbonitrile

2-(1,3-Oxazol-5-yl)pyridine N-oxide (1.0 g, 6.6 mmol) was dissolved innitroethane (15 ml), and trimethylsilyl cyanide (2.7 g, 27.2 mmol) andN,N-dimethylcarbamoyl chloride (3.0 g, 27.8 mmol) were added thereto.The mixture was stirred at room temperature for 5 days. The solvent wasevaporated, and the residue was subjected to a silica gel columnchromatography. The fractions eluted with ethyl acetate-hexane (1:1,v/v) were collected, concentrated and recrystallized from hexane-ethylacetate to give the titled compound (0.84 g, 75%).

mp. 147.8-148.1° C.

¹H-NMR (CDCl₃) δ: 7.62 (1H, dd, J=1.3, 7.3 Hz), 7.82 (1H, s), 7.86 (1H,dd, J=1.3, 8.1 Hz), 7.93 (1H, dd, J=7.3, 8.1 Hz), 8.01 (1H, s).

IR(KBr): 3163, 3063, 2235, 1597, 1574, 1496, 1448, 1122, 958, 814 cm⁻¹.

Elemental Analysis for C₉H₅N₃O

Calcd. C, 63.16; H, 2.94; N, 24.55.

Found C, 63.04; H, 2.65; N, 24.46.

Example 195

2-(1,3-Oxazol-5-yl)-2-pyridyl]-4H-1,3-benzothiazine-4-one

6-(1,3-Oxazol-5-yl)-2-pyridinecarbonitrile (0.72 g, 4.2 mmol) and methylthiosalicylate (1.54 g, 9.1 mmol) were dissolved in toluene (6 ml), andtriethylamine (1.5 ml, 10.7 mmol) was added thereto. The mixture wasrefluxed for 8 hrs. After cooling, the precipitates were collected byfiltration and recrystallized from hexane-chlorobenzene to give thetitled compound (1.24 g, 95%) as pale yellow crystals.

mp. 271.3-272.7° C.

¹H-NMR (DMSO-d₆) δ: 7.73 (1H, m), 7.83 (1H, m), 7.92 (1H, d, J=7.4 Hz),7.99 (1H, s), 8.09 (1H, d, J=7.4 Hz), 8.20 (1H, m), 8.29 (1H, d, J=7.4Hz), 8.35 (1H, d, J=7.7 Hz), 8.66 (1H, s).

IR(KBr): 3128, 2649, 1570, 1529, 1487, 1439, 1304, 1093, 815, 752 cm⁻¹.

Elemental Analysis for C₁₆H₉N₃O₂S

Calcd. C, 62.53; H, 2.95; N, 13.67.

Found C, 62.51; H, 2.66; N, 13.62.

Reference Example 65

6-(Pyrazol-1-yl)-2-pyridinecarbonitrile

6-Chloro-2-pyridinecarbonitrile (1.0 g, 7.2 mmol) and pyrazole (2.4 g,35.9 mmol) were dissolved in DMF (10 ml), and potassium carbonate (3.0g, 21.7 mmol) was added thereto. The mixture was stirred at 100° C. for18 hrs. The reaction mixture was combined with ethyl acetate and water,the organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated, and the residuewas subjected to a silica gel column chromatography. The fractionseluted with hexane-ethyl acetate (3:1, v/v) were collected, concentratedand recrystallized from hexane-ethyl acetate to give the titled compound(0.98 g, 80%).

mp. 120.9-122.1° C.

¹H-NMR (CDCl₃) δ: 6.51 (1H, m), 7.57 (1H, d, J=7.4 Hz), 7.76 (1H, d,J=0.6 Hz), 7.94 (1H, m), 8.24 (1H, d, J=8.4 Hz), 8.56 (1H, d, J=2.5 Hz).

IR(KBr): 3092, 2235, 1593, 1527, 1469, 1392, 945, 806, 750 cm⁻¹.

Elemental Analysis for C₉H₆N₄

Calcd. C, 63.52; H, 3.55; N, 32.92.

Found C, 63.51; H, 3.34; N, 32.68.

Example 196

2-[6-(1H-Pyrazol-1-yl)-2-pyridyl]-4H-1,3-benzothiazine-4-on e

6-(Pyrazol-1-yl)-2-pyridinecarbonitrile (0.68 g, 4.0 mmol) and methylthiosalicylate (1.00 g, 5.9 mmol) were dissolved in toluene (5 ml), andtriethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture wasrefluxed for 8 hrs. After cooling, the precipitates were collected byfiltration and recrystallized from hexane-tetrahydrofuran to give thetitled compound (0.82 g, 67%) as pale yellow crystals.

mp. 253.0-254.0° C.

¹H-NMR (CDCl₃) δ: 6.56 (1H, m), 7.62-7.73 (3H, m), 7.80 (1H, s), 8.02(1H, dd, J=7.8, 7.8 Hz), 8.22 (1H, d, J=7.8 Hz), 8.41 (1H, d, J=7.5 Hz),8.55 (1H, m), 8.72 (1H, d, J=2.5 Hz).

IR(KBr): 3074, 1658, 1574, 1537, 1469, 1402, 1060, 933, 814, 742 cm⁻¹.

Elemental Analysis for C₁₆H₁₀N₄OS

Calcd. C, 62.73; H, 3.29; N, 18.29.

Found C, 62.73; H, 3.06; N, 18.26.

Reference Example 66

6-Phenyl-2-pyridinecarbonitrile

6-Chloro-2-pyridinecarbonitrile (0.80 g, 5.7 mmol) and phenylboric acid(1.05 g, 8.6 mmol) were dissolved in toluene (60 ml)-ethanol (15 ml),and potassium carbonate (2.00 g, 14.4 mmol) and water (15 ml) were addedthereto. The mixture was deairated under reduced pressure for 10minutes. Tetrakis(triphenylphosphine)palladium (0) (0.33 g, 0.29 mmol)was added to the reaction mixture under argon atmosphere, and themixture was refluxed for 16 hrs. The reaction mixture was combined withethyl acetate and water. The organic layer was washed with saturatedbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated, and the residue was subjected to a silica gel columnchromatography. The fractions eluted with hexane-ethyl acetate (4:1,v/v) were collected, concentrated and recrystallized from hexane-ethylacetate to give the titled compound (0.90 g, 86%).

mp. 65.2-66.1° C.

¹H-NMR (CDCl₃) δ: 7.48-7.51 (3H, m), 7.62 (1H, dd, J=1.1, 7.3 Hz),7.85-7.93 (2H, m), 8.01-8.04 (2H, m)

IR(KBr): 3067, 2235, 1581, 1556, 1448, 817, 762 cm⁻¹.

Elemental Analysis for C₁₂H₈N₂

Calcd. C, 79.98; H, 4.47; N, 15.55.

Found C, 79.86; H, 4.61; N, 15.42.

Reference Example 67

6-(4-Methoxyphenyl)-2-pyridinecarbonitrile

6-Chloro-2-pyridinecarbonitrile (0.70 g, 5.0 mmol) and4-methoxyphenylboric acid (1.17 g, 7.7 mmol) were dissolved in toluene(60 ml)-ethanol (15 ml), and potassium carbonate (1.75 g, 12.6 mmol) andwater (15 ml) were added thereto. The mixture was deairated underreduced pressure for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.29 g, 0.25 mmol) was added to the reaction mixture under argonatmosphere, and the mixture was refluxed for 16 hrs. The reactionmixture was combined with ethyl acetate and water. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated, and the residue was subjected to a silicagel column chromatography. The fractions eluted with hexane-ethylacetate (4:1, v/v) were collected, concentrated and recrystallized fromhexane-ethyl acetate to give the titled compound (0.94 g, 88%).

mp. 86.3-86.6° C.

¹H-NMR (CDCl₃) δ: 3.46 (3H, s), 7.01 (2H, m), 7.54 (1H, dd, J=1.3, 7.1Hz), 7.79-7.89 (2H, m), 8.00 (2H, m)

IR(KBr): 2972, 2235, 1608, 1585, 1518, 1448, 1440, 1315, 1265, 1178,1024 cm⁻¹.

Elemental Analysis for C₁₃H₁₀N₂O

Calcd. C, 74.27; H, 4.79; N, 13.33.

Found C, 74.39; H, 5.00; N, 13.14.

Example 197

2-(6-Phenyl-2-pyridyl)-4H-1,3-benzothiazine-4-one

6-Phenyl-2-pyridinecarbonitrile (0.72 g, 4.0 mmol) and methylthiosalicylate (1.20 g, 7.1 mmol) were dissolved in toluene (4 ml), andtriethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture wasrefluxed for 8 hrs. After cooling, the precipitates were collected byfiltration and recrystallized from hexane-tetrahydrofuran to give thetitled compound (0.73 g, 57%) as white crystals.

mp. 195.4-197.0° C.

¹H-NMR (CDCl₃) δ: 7.46-7.57 (3H, m), 7.62-7.69 (3H, m), 7.95-7.97 (2H,m), 8.16 (2H, d, J=7.0 Hz), 8.45 (1H, dd, J=1.8, 6.6 Hz), 8.56 (1H, d,J=7.5 Hz).

IR(KBr): 3063, 1658, 1572, 1537, 1446, 1296, 1234, 1097, 956, 763 cm⁻¹.

Elemental Analysis for C₁₉H₁₂N₂OS

Calcd. C, 72.13; H, 3.82; N, 8.85.

Found C, 72.29; H, 3.75; N, 8.81.

Example 198

2-[6-(4-Methoxyphenyl)-2-pyridyl]-4H-1,3-benzothiazine-4-on e

6-(4-Methoxyphenyl)-2-pyridinecarbonitrile (0.81 g, 3.8 mmol) and methylthiosalicylate (1.07 g, 6.3 mmol) were dissolved in toluene (4 ml), andtriethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture wasrefluxed for 8 hrs. After cooling, the precipitates were collected byfiltration and recrystallized from hexane-tetrahydrofuran to give thetitled compound (0.87 g, 65%) as pale yellow crystals.

mp. 200.1-201.1° C.

¹H-NMR (CDCl₃) δ: 3.90 (3H, s), 7.06 (2H, d, J=8.8 Hz), 7.59-7.69 (3H,m), 7.89-7.91 (2H, m), 8.13 (2H, d, J=8.8 Hz), 8.36 (1H, m), 8.56 (1H,d, J=7.7 Hz).

IR(KBr): 3067, 3003, 2982, 2835, 1657, 1574, 1531, 1518, 1450, 1313,1257 cm⁻¹.

Elemental Analysis for C₂₀H₁₄N₂O₂S

Calcd. C, 69.35; H, 4.07; N, 8.09.

Found C, 69.26; H, 4.01; N, 7.92.

Reference Example 68

6-Cyano-2,2′-bipyridyl

2,2′-Bipyridyl N-oxide (2.8 g, 16 mmol) was dissolved in nitroethane (50ml), and trimethylsilyl cyanide (6.4 g, 65 mmol) andN,N-dimethylcarbamoyl chloride (3.7 g, 35 mmol) were added thereto. Themixture was stirred at room temperature for 36 hrs. The solvent wasevaporated, and the residue was subjected to a silica gel columnchromatography. The fractions eluted with hexane-ethyl acetate (3:1,v/v) were collected, concentrated and recrystallized from hexane-ethylacetate to give the titled compound (1.2 g, 43%) as white crystals.

mp. 135.9-136.8° C.

¹H-NMR (CDCl₃) δ: 7.37 (1H, m) 7.70 (1H, dd, J=0.9, 7.6 Hz), 7.86 (1H,m), 7.95 (1H, m), 8.47 (1H, dd, J=0.9, 7.9 Hz), 8.65-8.70 (2H, m).

IR(KBr): 3491, 2237, 1581, 1431, 987, 775 cm⁻¹.

Elemental Analysis for C₁₁H₇N₃

Calcd. C, 72.92; H, 3.89; N, 23.19.

Found C, 72.80; H, 3.81; N, 22.97.

Example 199

2-[6-(2,2′-Bipyridyl)]-4H-1,3-benzothiazine-4-one

6-Cyano-2,2′-bipyridyl (0.90 g, 4.9 mmol) and methyl thiosalicylate(1.26 g, 7.5 mmol) were dissolved in toluene (5 ml), and triethylamine(2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 12hrs. After cooling, the precipitates were collected by filtration andrecrystallized from hexane-tetrahydrofuran to give the titled compound(1.34 g, 85%) as white crystals.

mp. 222.1-223.9° C.

¹H-NMR (CDCl₃) δ: 7.38 (1H, m), 7.60-7.72 (3H, m), 7.92 (1H, m), 8.02(1H, m), 8.51-8.73 (5H, m).

IR(KBr): 3520, 3063, 1666, 1574, 1537, 1431, 1313, 1284, 779 cm⁻¹.

Elemental Analysis for C₁₈H₁₁N₃OS

Calcd. C, 68.12; H, 3.49; N, 13.24.

Found C, 67.90; H, 3.30; N, 13.10.

Reference Example 69

4,4′-Dimethyl-2,2′-bipyridyl N-oxide

4,4′-Dimethyl-2,2′-bipyridyl (4.8 g, 26 mmol) and 3-chloroperbenzoicacid (77%, 8.7 g, 39 mmol) were dissolved in chloroform (25 ml), and themixture was stirred at room temperature for 24 hrs. The solvent wasevaporated, and the residue was subjected to a silica gel columnchromatography. The fractions eluted with ethylacetate-methanol (4:1,v/v) were collected, concentrated and crystallized from dimethyl etherto give the titled compound (3.7 g, 71%).

¹H-NMR (CDCl₃) δ: 2.39 (3H, s), 2.44 (3H, s), 7.06 (1H, dd, J=2.5, 6.7Hz), 7.16 (1H, dd, J=0.7, 4.9 Hz), 7.93 (1H, d, J=2.5 Hz), 8.20 (1H, d,J=6.7 Hz), 8.56 (1H, d, J=4.9 Hz), 8.72 (1H, s).

Reference Example 70

6-Cyano-4,4′-dimethyl-2,2′-bipyridyl

4,4′-Dimethyl-2,2′-bipyridyl N-oxide (3.7 g, 18 mmol) was dissolved innitroethane (50 ml), and trimethylsilyl cyanide (5.5 g, 55 mmol) andN,N-dimethylcarbamoyl chloride (2.9 g, 27 mmol) were added thereto. Themixture was stirred at room temperature for 36 hrs. The solvent wasevaporated, and the residue was subjected to a silica gel columnchromatography. The fractions eluted with hexane-ethyl acetate (5:1,v/v) were collected, concentrated and recrystallized from hexane-ethylacetate to give the titled compound (3.4 g, 87%) as white crystals.

mp. 132.1-132.4° C.

¹H-NMR (CDCl₃) δ: 2.46 (3H, s), 2.49 (3H, s), 7.18 (1H, dd, J=0.9, 4.9Hz), 7.51 (1H, d, J=0.6 Hz), 8.28 (1H, d, J=0.9 Hz), 8.47 (1H, d, J=0.6Hz), 8.52 (1H, d, J=4.9 Hz).

IR(KBr): 2918, 2231, 1597, 1554, 1377, 991, 871, 833 cm⁻¹.

Elemental Analysis for C₁₃H₁₁N₃

Calcd. C, 74.62; H, 5.30; N, 20.08.

Found C, 74.62; H, 5.20; N, 20.06.

Example 200

2-[6-(4,4′-Dimethyl-2,2′-bipyridyl)]-4H-1,3-benzothiazine-4-one

6-Cyano-4,4′-dimethyl-2,2′-bipyridyl (1.00 g, 4.8 mmol) and methylthiosalicylate (1.25 g, 7.4 mmol) were dissolved in toluene (5 ml), andtriethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture wasrefluxed for 9 hrs. After cooling, the precipitates were collected byfiltration and recrystallized from hexane-tetrahydrofuran to give thetitled compound (1.22 g, 74%) as white crystals.

mp. 234.9-235.2° C.

¹H-NMR (CDCl₃) δ: 2.53 (3H, s), 2.54 (3H, s), 7.20 (1H, m) 7.61-7.70(3H, m), 8.38 (2H, m), 8.48 (1H, s), 8.55-8.58 (2H, m).

IR(KBr): 3051, 1660, 1593, 1572, 1537, 1439, 1298, 1284, 1095, 738 cm⁻¹.

Elemental Analysis for C₂₀H₁₅N₃OS

Calcd. C, 69.54; H, 4.38; N, 12.17.

Found C, 69.44; H, 4.29; N, 12.17.

Example 201

N-(2-Hydroxyethyl)-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridinecarboxamide

6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridinecarboxyl ic acid (1.00 g,3.5 mmol) was dissolved in DMF (20 ml). 2-Aminoethanol (0.51 g, 8.3mmol), WSC (1.34 g, 7.0 mmol) and HOBt (0.95 g, 7.0 mmol) were addedthereto, and the mixture was stirred at 80° C. for 6 hrs. The reactionmixture was combined with ethyl acetate and water. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated, and the residue was subjected to a silicagel column chromatography. The fractions eluted with ethylacetate-methanol (4:1, v/v) were collected, concentrated andrecrystallized from diisopropyl ether-methanol to give the titledcompound (0.12 g, 10%) as pale yellow crystals.

mp. 213.8-215.2° C.

¹H-NMR (DMSO-d₆) δ: 3.51 (2H, dt, J=5.7, 5.6 Hz), 3.62 (2H, t, J=5.7Hz), 4.89 (1H, br s), 7.75 (1H, m), 7.83-7.90 (2H, m), 8.25-8.39 (3H,m), 8.50 (1H, m), 8.55 (1H, t, J=5.6 Hz).

IR(KBr): 3383, 3327, 2949, 2934, 1657, 1535, 1439, 1300, 1093, 748 cm⁻¹.

Elemental Analysis for C₁₆H₁₃N₃O₃S

Calcd. C, 58.70; H, 4.00; N, 12.84.

Found C, 58.48; H, 3.87; N, 12.64.

Reference Example 71

tert-Butyl 2-pyridylmethylcarbamate

2-Aminomethylpyridine (6.0 g, 55 mmol) and di-tert-butyl dicarbonate(13.3 g, 61 mmol) were dissolved in tetrahydrofuran (150 ml), and themixture was stirred at 0° C. for 1 hr and at room temperature for 3 hrs.The solvent was evaporated and the residue was subjected to a silica gelcolumn chromatography. The fractions eluted with hexane-ethyl acetate(2:3, v/v) were collected and concentrated to give the titled compound(11.4 g, 98%)

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 4.44 (2H, d, J=5.3 Hz), 5.57 (1H, br s),7.17 (1H, dd, J=5.0, 7.3 Hz), 7.27 (1H, d, J=6.0 Hz), 7.65 (1H, m), 8.53(1H, d, J=5.0 Hz)

Reference Example 72

tert-Butyl 2-pyridylmethylcarbamate N-oxide

tert-Butyl 2-pyridylmethylcarbamate (11.4 g, 54 mmol) and3-chloroperbenzoic acid (77%, 5.9 g, 71 mmol) were dissolved in ethylacetate (150 ml), and the mixture was stirred at room temperature for 15hrs. The solvent was evaporated, and the residue was subjected to asilica gel column chromatography. The fractions eluted withmethanol-ethyl acetate (1:5, v/v) were collected and concentrated togive the titled compound (11.1 g, 90%).

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 4.47 (2H, d, J=6.4 Hz), 5.88 (1H, br s),7.22-7.25 (2H, m), 7.40 (1H, m), 8.23 (1H, m).

Reference Example 73

tert-Butyl (6-cyano-2-pyridyl)methylcarbamate

tert-Butyl 2-pyridylmethylcarbamate N-oxide (3.0 g, 13.3 mmol) wasdissolved in nitroethane (50 ml), and trimethylsilyl cyanide (2.8 g,28.6 mmol) and N,N-dimethylcarbamoyl chloride (1.7 g, 16.2 mmol) wereadded thereto. The mixture was stirred at room temperature for 24 hrs.The solvent was evaporated, and the residue was subjected to a silicagel column chromatography. The fractions eluted with ethylacetate-hexane (2:1, v/v) were collected, concentrated andrecrystallized from hexane-ethyl acetate to give the titled compound(1.8 g, 58%) as white crystals.

mp. 85.9-86.5° C.

¹H-NMR (CDCl₃) δ: 1.46 (9H, s) 4.47 (2H, d, J=5.7 Hz), 5.48 (1H, br s),7.51 (1H, d, J=7.8 Hz), 7.59 (1H, d, J=7.3 Hz), 7.81 (1H, dd, J=7.3, 7.8Hz).

IR(KBr): 3350, 2978, 2237, 1712, 1693, 1514, 1452, 1367, 1282, 1250,1171 cm⁻¹.

Elemental Analysis for C₁₂H₁₅N₃O₂

Calcd. C, 61.79; H, 6.48; N, 18.01.

Found C, 61.79; H, 6.59; N, 18.01.

Example 202

tert-Butyl [6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methylcarbamate

tert-Butyl (6-cyano-2-pyridyl)methylcarbamate (1.6 g, 6.8 mmol) andmethyl thiosalicylate (1.8 g, 10.9 mmol) were dissolved in toluene (6ml), and triethylamine (3.0 ml, 21.5 mmol) was added thereto. Themixture was refluxed for 20 hrs. After cooling, the precipitates werecollected by filtration and dissolved in chloroform. The solution wassubjected to a silica gel column chromatography. The fractions elutedwith chloroform-methanol (20:1, v/v) were collected, concentrated andrecrystallized from hexane-chloroform to give the titled compound (1.8g, 72%) as pale yellow crystals.

mp. 160.0-162.1° C.

¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 4.57 (2H, d, J=5.7 Hz), 5.47 (1H, br s),7.51 (1H, d, J=7.7 Hz), 7.60-7.71 (3H, m), 7.87 (1H, m), 8.42 (1H, d,J=7.7 Hz), 8.54 (1H, m).

IR(KBr): 3350, 2976, 1711, 1658, 1572, 1537, 1439, 1290, 1250, 1170,1097 cm⁻¹.

Elemental Analysis for C₁₉H₁₉N₃O₃S

Calcd. C, 61.77; H, 5.18; N, 11.37.

Found C, 61.54; H, 5.00; N, 11.30.

Example 203

2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroaceticacid salt

tert-Butyl (6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methylcarbamate (0.25 g, 0.67 mmol) was dissolved in trifluoroacetic acid (4 ml), andthe mixture was stirred at room temperature for 2 hrs. The solvent wasevaporated and the residue was recrystallized from methanol-diisopropylether to give the titled compound (0.22 g, 85%) as white crystals.

mp. 184.5-186.5° C.

¹H-NMR (DMSO-d₆) δ: 4.39 (2H, s), 7.75 (1H, m), 7.83-7.88 (3H, m), 8.19(1H, m), 8.34-8.40 (2H, m), 8.55 (3H, s).

IR(KBr): 3535, 2995, 1685, 1647, 1527, 1201, 1128, 796 cm⁻¹.

Elemental Analysis for C₁₆H₁₂N₃O₃SF₃ 0.25H₂O

Calcd. C, 49.55; H, 3.25; N, 10.83.

Found C, 49.58; H, 3.26; N, 10.83.

Example 204

N-[[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methyl]ace tamide

2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroaceticacid salt (350 mg, 0.91 mmol) was dissolved in N,N-dimethylacetamide (10ml), and acetyl chloride (150 mg, 1.91 mmol) was added thereto. Thereaction mixture was stirred at 60° C. for 3 hrs and combined with ethylacetate, tetrahydrofuran and water. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated, and the residue was subjected to a silica gel columnchromatography. The fractions eluted with methanol-ethyl acetate (1:10,v/v) were collected, concentrated and recrystallized frommethanol-diisopropyl ether to give the titled compound (81 mg, 28%) aswhite crystals.

mp. 199.2-200.4° C.

¹H-NMR (CDCl₃) δ: 2.17 (3H, s) 4.69 (2H, d, J=5.3 Hz), 6.73 (1H, br s),7.51 (1H, d, J=7.6 Hz), 7.58-7.69 (3H, m), 7.85 (1H, m), 8.38 (1H, d,J=7.7 Hz), 8.54 (1H, dd, J=1.8, 7.4 Hz).

IR(KBr): 3285, 3080, 1651, 1572, 1537, 1294, 738 cm⁻¹.

Elemental Analysis for C₁₆H₁₃N₃O₂S

Calcd. C, 61.72; H, 4.21; N, 13.50.

Found C, 61.59; H, 4.18; N, 13.26.

Example 205

N-[[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methyl]pro panamide

2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroaceticacid salt (500 mg, 1.3 mmol) was dissolved in N,N-dimethylacetamide (10ml), and propionyl chloride (370 mg, 4.0 mmol) was added thereto. Thereaction mixture was stirred at 60° C. for 16 hrs and combined withethyl acetate and water. The organic layer was washed with saturatedbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated, and the residue was subjected to a silica gel columnchromatography. The fractions eluted with methanol-ethyl acetate (1:20,v/v) were collected, concentrated and recrystallized fromhexane-tetrahydrofuran to give the titled compound (224 mg, 53%) aswhite crystals.

mp. 199.0-199.8° C.

¹H-NMR (CDCl₃) δ: 1.29 (3H, t, J=7.5 Hz), 2.42 (2H, q, J=7.5 Hz) 4.70(2H, d, J=5.2 Hz), 6.74 (1H, br s), 7.51 (1H, d, J=7.6 Hz), 7.60-7.70(3H, m), 7.86 (1H, m), 8.39 (1H, d, J=7.6 Hz), 8.54 (1H, m).

IR(KBr): 3285, 3071, 1651, 1572, 1537, 1439, 1302, 1236, 734 cm⁻¹.

Elemental Analysis for C₁₇H₁₅N₃O₂S

Calcd. C, 62.75; H, 4.65; N, 12.91.

Found C, 62.74; H, 4.89; N, 12.86.

Example 206

2-Methyl-N-[[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methyl]propanamide

2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroaceticacid salt (450 mg, 1.1 mmol) was dissolved in N,N-dimethylacetamide (10ml), and isobutyryl chloride (365 mg, 3.9 mmol) was added thereto. Thereaction mixture was stirred at 60° C. for 16 hrs and combined withethyl acetate and water. The organic layer was washed with saturatedbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated, and the residue was subjected to a silica gel columnchromatography. The fractions eluted with methanol-ethyl acetate (1:30,v/v) were collected, concentrated and recrystallized from hexane-ethanolto give the titled compound (231 mg, 58%) as white crystals.

mp. 188.6-189.2° C.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 2.58 (1H, sept, J=6.9 Hz) 4.70(2H, d, J=5.1 Hz), 6.79 (1H, br s), 7.50 (1H, d, J=7.7 Hz), 7.58-7.70(3H, m), 7.87 (1H, m), 8.41 (1H, d, J=7.7 Hz), 8.55 (1H, m).

IR(KBr): 3433, 3273, 3071, 2966, 1649, 1589, 1572, 1537, 1440, 1302,1240 cm⁻¹.

Elemental Analysis for C₁₈H₁₇N₃O₂S·1.0H₂O

Calcd. C, 60.49; H, 5.36; N, 11.76.

Found C, 60.74; H, 5.27; N, 11.72.

Example 207

N-[[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methyl]ben zamide

2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroaceticacid salt (330 mg, 0.86 mmol) was dissolved in N,N-dimethylacetamide (10ml), and benzoyl chloride (264 mg, 1.87 mmol) was added thereto. Thereaction mixture was stirred at 60° C. for 14 hrs and combined withethyl acetate and water. The organic layer was washed with saturatedbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated, and the residue was subjected to a silica gel columnchromatography. The fractions eluted with hexane-ethyl acetate (1:3,v/v) were collected, concentrated and recrystallized fromhexane-tetrahydrofuran to give the titled compound (125 mg, 39%) aswhite crystals.

mp. 213.9-214.7° C.

¹H-NMR (CDCl₃) δ: 4.90 (2H, d, J=5.1 Hz), 7.51-7.67 (8H, m), 7.88 (1H,m), 8.00 (2H, m), 8.31 (1H, d, J=7.7 Hz), 8.54 (1H, m).

IR(KBr): 3344, 1651, 1572, 1537, 1296, 754 cm⁻¹.

Elemental Analysis for C₂₁H₁₅N₃O₂S

Calcd. C, 67.54; H, 4.05; N, 11.25.

Found C, 67.35; H, 4.13; N, 11.16.

Example 208

N-[[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methyl]-2-thiophenecarboxamide

2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroaceticacid salt (350 mg, 0.91 mmol) was dissolved in N,N-dimethylacetamide (10ml), and 2-thenoyl chloride (400 mg, 2.72 mmol) was added thereto. Thereaction mixture was stirred at 60° C. for 15 hrs and combined withethyl acetate and water. The organic layer was washed with saturatedbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated, and the residue was subjected to a silica gel columnchromatography. The fractions eluted with hexane-ethylacetate (1:4, v/v)were collected, concentrated and recrystallized fromhexane-tetrahydrofuran to give the titled compound (151 mg, 43%) aswhite crystals.

mp. 208.5-209.0° C.

¹H-NMR (CDCl₃) δ: 4.86 (2H, d, J=5.1 Hz), 7.16 (1H, dd, J=3.7, 4.9 Hz),7.45 (1H, m), 7.52-7.57 (3H, m), 7.60-7.69 (2H, m), 7.75 (1H, dd, J=1.1,3.7 Hz), 7.88 (1H, m), 8.37 (1H, d, J=7.5 Hz), 8.53 (1H, m).

IR(KBr) 3325, 1643, 1572, 1531, 1298, 1267, 734 cm⁻¹.

Elemental Analysis for C₁₉H₁₃N₃O₂S₂

Calcd. C, 60.14; H, 3.45; N, 11.07.

Found C, 60.11; H, 3.41; N, 11.17.

Example 209

2,2,2-Trifluoro-N-[[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methyl)acetamide

2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroaceticacid salt (350 mg, 0.91 mmol) was dissolved in pyridine (10 ml), andmethanesulfonyl chloride (576 mg, 5.04 mmol) was added thereto. Thereaction mixture was stirred at room temperature for 3 hrs. The solventwas evaporated, and the residue was subjected to a silica gel columnchromatography. The fractions eluted with hexane-ethyl acetate (1:1,v/v) were collected, concentrated and recrystallized fromhexane-tetrahydrofuran to give the titled compound (228 mg, 68%) as paleyellow crystals.

mp. 226.4-227.4° C.

¹H-NMR (CDCl₃) δ: 4.80 (2H, d, J=5.0 Hz), 7.51 (1H, d, J=7.7 Hz), 7.59(1H, m), 7.64-7.71 (2H, m), 7.88-7.93 (2H, m), 8.42 (1H, d, J=7.7 Hz),8.54 (1H, dd, J=1.8, 7.5 Hz).

IR(KBr): 3269, 3105, 1711, 1655, 1570, 1533, 1439, 1298, 1174, 738 cm⁻¹.

Elemental Analysis for C₁₆H₁₀N₃O₂SF₃

Calcd. C, 52.60; H, 2.78; N, 11.50.

Found C, 52.74; H, 2.95; N, 11.55.

Example 210

3-(Methylthio)-N-[[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methyl]propanamide

2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroaceticacid salt (0.80 g, 2.1 mmol) was dissolved in N,N-dimethylacetamide (10ml), and 3-methylthiopropionyl chloride (0.86 g, 6.2 mmol) was addedthereto. The reaction mixture was stirred at 60° C. for 15 hrs andcombined with ethyl acetate and water. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated, and the residue was subjected to a silica gel columnchromatography. The fractions eluted with methanol-ethyl acetate (1:10,v/v) were collected, concentrated and recrystallized from diisopropylether-tetrahydrofuran to give the titled compound (0.18 g, 24%) as whitecrystals.

mp. 191.6-192.8° C.

¹H-NMR (CDCl₃) δ: 2.18 (3H, s), 2.69 (2H, t, J=7.0 Hz), 2.92 (2H, t,J=7.0 Hz), 4.72 (2H, d, J=5.2 Hz), 6.95 (1H, m), 7.53 (1H, d, J=7.7 Hz),7.61-7.70 (3H, m), 7.86 (1H, m), 8.39 (1H, d, J=7.8 Hz), 8.55 (1H, m).

IR(KBr): 3283, 3078, 1660, 1651, 1572, 1531, 1440, 1300, 1097, 734 cm⁻¹.

Elemental Analysis for C₁₈H₁₇N₃O₂S₂

Calcd. C, 58.20; H, 4.61; N, 11.31.

Found C, 58.05; H, 4.48; N, 11.30.

Example 211

N-[[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methyl]methanesulfonamide

2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroaceticacid salt (450 mg, 1.1 mmol) and methanesulfonyl chloride (205 mg, 1.7mmol) were dissolved in ethyl acetate (10 ml) and water (5 ml), andsodium hydrogen carbonate (250 mg, 3.0 mmol) was added thereto. Themixture was stirred at room temperature for 1 hr. The reaction mixturewas combined with ethyl acetate and water. The organic layer was washedwith saturated brine and dried over anhydrous magnesium sulfate. Thesolvent was evaporated, and the residue was subjected to a silica gelcolumn chromatography. The fractions eluted with ethyl acetate-methanol(20:1, v/v) were collected, concentrated and recrystallized fromhexane-tetrahydrofuran to give the titled compound (88 mg, 21%) as whitecrystals.

mp. 188.1-189.5° C.

¹H-NMR (CDCl₃) δ: 3.03 (3H, s), 4.60 (2H, d, J=5.7 Hz), 5.64 (1H, m),7.56 (1H, d, J=7.7 Hz), 7.60-7.71 (3H, m), 7.91 (1H, m), 8.46 (1H, d,J=7.7 Hz), 8.54 (1H, m).

IR(KBr): 3271, 1658, 1572, 1531, 1440, 1317, 1149, 1097, 748, 736 cm⁻¹.

Elemental Analysis for C₁₅H₁₃N₃O₃S₂

Calcd. C, 51.86; H, 3.77; N, 12.10.

Found C, 51.76; H, 3.69; N, 12.00.

Example 212

N-[[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methyl]ethanesulfonamide

2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroaceticacid salt (500 mg, 1.3 mmol) and ethanesulfonyl chloride (270 mg, 2.1mmol) were dissolved in ethyl acetate (10 ml) and water (5 ml), andsodium hydrogen carbonate (270 mg, 3.2 mmol) was added thereto. Themixture was stirred at room temperature for 3 hrs. The reaction mixturewas combined with ethyl acetate and water. The organic layer was washedwith saturated brine and dried over anhydrous magnesium sulfate. Thesolvent was evaporated, and the residue was subjected to a silica gelcolumn chromatography. The fractions eluted with ethyl acetate-hexane(2:1, v/v) were collected, concentrated and recrystallized fromhexane-tetrahydrofuran to give the titled compound (101 mg, 21%) as paleyellow crystals.

mp. 170.0-171.0° C.

¹H-NMR (CDCl₃) δ: 1.41 (3H, t, J=7.3 Hz), 3.11 (2H, q, J=7.3 Hz), 4.58(2H, d, J=5.7 Hz), 5.52 (1H, t, J=5.7 Hz), 7.56 (1H, d, J=7.7 Hz),7.61-7.71 (3H, m), 7.91 (1H, m), 8.46 (1H, d, J=7.8 Hz), 8.55 (1H, m).

IR(KBr): 3269, 1658, 1572, 1531, 1440, 1319, 1143, 1097, 736 cm⁻¹.

Elemental Analysis for C₁₆H₁₅N₃O₃S₂

Calcd. C, 53.17; H, 4.18; N, 11.63.

Found C, 53.19; H, 4.32; N, 11.71.

Example 213

N-[[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methyl]benzenesulfonamide

2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroaceticacid salt (400 mg, 1.0 mmol) and benzenesulfonyl chloride (300 mg, 1.7mmol) were dissolved in ethyl acetate (10 ml) and water (5 ml), andsodium hydrogen carbonate (225 mg, 2.6 mmol) was added thereto. Themixture was stirred at room temperature for 2 hrs. The reaction mixturewas combined with ethyl acetate and water. The organic layer was washedwith saturated brine and dried over anhydrous magnesium sulfate. Thesolvent was evaporated, and the residue was subjected to a silica gelcolumn chromatography. The fractions eluted with ethyl acetate-hexane(1:1, v/v) were collected, concentrated and recrystallized fromhexane-tetrahydrofuran to give the titled compound (162 mg, 38%) aswhite crystals.

mp. 206.7-207.5° C.

¹H-NMR (CDCl₃) δ: 4.44 (2H, d, J=5.7 Hz), 5.84 (1H, t, J=5.7 Hz),7.38-7.49 (4H, m), 7.65-7.70 (3H, m), 7.79 (1H, m), 7.86-7.90 (2H, m),8.35 (1H, d, J=7.5 Hz), 8.55 (1H, m)

IR(KBr): 3254, 3063, 1658, 1651, 1572, 1537, 1444, 1327, 1304, 1161,1095 cm⁻¹.

Elemental Analysis for C₂₀H₁₅N₃O₃S₂

Calcd. C, 58.66; H, 3.69; N, 10.26.

Found C, 58.70; H, 3.67; N, 10.13.

Example 214

Diethyl [6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methylamidophosphate

2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroaceticacid salt (400 mg, 1.0 mmol) and diethyl chlorophosphate (360 mg, 2.1mmol) were dissolved in acetonitrile (15 ml), and potassium carbonate(430 mg, 3.1 mmol) was added thereto. The mixture was stirred at roomtemperature for 15 hrs. The solvent was evaporated, and the residue wassubjected to a silica gel column chromatography. The fractions elutedwith ethyl acetate-methanol (8:1, v/v) were collected, concentrated andrecrystallized from diisopropyl ether-methanol to give the titledcompound (225 mg, 53%) as white crystals.

mp. 135.2-135.8° C.

¹H-NMR (CDCl₃) δ: 1.36 (6H, m), 3.84 (1H, m), 4.13 (4H, m), 4.37 (2H,dd, J=6.3, 9.1 Hz), 7.55 (1H, d, J=7.7 Hz), 7.63-7.71 (3H, m), 7.89 (1H,m), 8.45 (1H, d, J=7.7 Hz), 8.55 (1H, m).

IR(KBr): 3223, 2982, 1660, 1572, 1537, 1440, 1300, 1236, 1057, 1030, 966cm⁻¹.

Elemental Analysis for C₁₈H₂₀N₃O₄SP

Calcd. C, 53.33; H, 4.97; N, 10.36.

Found C, 53.18; H, 4.87; N, 10.65.

Example 215

O,O-Diethyl [6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methylamidothiophosphate

2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroaceticacid salt (400 mg, 1.0 mmol) and diethyl chlorothiophosphate (410 mg,2.2 mmol) were dissolved in acetonitrile (15 ml), and potassiumcarbonate (430 mg, 3.1 mmol) was added thereto. The mixture was stirredat room temperature for 2 hrs. The solvent was evaporated, and theresidue was subjected to a silica gel column chromatography. Thefractions eluted with ethyl acetate-hexane (1:2, v/v) were collected,concentrated and recrystallized from ethyl acetate-hexane to give thetitled compound (362 mg, 82%) as white crystals.

mp. 132.3-133.3° C.

¹H-NMR (CDCl₃) δ: 1.31 (6H, t, J=7.1 Hz), 4.03-4.18 (5H, m), 4.42 (2H,dd, J=6.4, 10.7 Hz), 7.56 (1H, d, J=7.7 Hz), 7.61-7.71 (3H, m), 7.89(1H, m), 8.45 (1H, d, J=7.7 Hz), 8.56 (1H, m).

IR(KBr): 3283, 2982, 1651, 1572, 1535, 1439, 1302, 1097, 1049, 1024, 956cm⁻¹.

Elemental Analysis for C₁₈H₂₀N₃O₃S₂P

Calcd. C, 51.29; H, 4.78; N, 9.97.

Found C, 51.32; H, 4.78; N, 10.00.

Example 216

N,N-Dimethyl-N′-[[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methyl]urea

A mixture of 2-[6-(aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-onetrifluoroacetic acid salt (0.40 g, 1.0 mmol) and potassium carbonate(0.43 g, 3.1 mmol) was stirred at room temperature for 20 minutes.Successively, N,N-dimethylcarbamoyl chloride (0.47 g, 4.3 mmol) wasadded to the mixture, and the mixture was stirred at room temperaturefor 5 hrs. The precipitates were filtered, and the filtrate wasconcentrated. The residue was subjected to a silica gel columnchromatography. The fractions eluted with chloroform-ethanol (40:1, v/v)were collected, concentrated and recrystallized from chloroform-hexaneto give the titled compound (0.24 g, 68%) as white crystals.

mp. 175.2-176.3° C.

¹H-NMR (CDCl₃) δ: 3.07 (6H, s), 4.69 (2H, s), 5.75 (1H, br s), 7.53-7.70(4H, m), 7.88 (1H, m), 8.42 (1H, d, J=7.7 Hz), 8.56 (1H, m).

IR(KBr): 3350, 2828, 1643, 1572, 1529, 1440, 1298, 1234, 1097, 734 cm⁻¹.

Elemental Analysis for C₁₇H₁₆N₄O₂S·0.5H₂O

Calcd. C, 58.44; H, 4.90; N, 16.03.

Found C, 58.58; H, 4.63; N, 16.01.

Reference Example 74

tert-Butyl 2-(2-pyridyl)ethylcarbamate

2-(2-Aminoethyl)pyridine (10.2 g, 83 mmol) and di-tert-butyl dicarbonate(20.0 g, 91 mmol) were dissolved in tetrahydrofuran (130 ml), and themixture was stirred at 0° C. for 30 minutes and at room temperature for3 hrs. The solvent was evaporated, and the residue was subjected to asilica gel column chromatography. The fraction eluted with hexane-ethylacetate (1:2, v/v) were collected and concentrated to give the titledcompound (18.5 g, 99%).

¹H-NMR (CDCl₃) δ: 1.43 (9H, s), 2.97 (2H, t, J=6.4 Hz), 3.54 (2H, m),5.15 (1H, br s), 7.12-7.17 (2H, m), 7.61 (1H, m), 8.53 (1H, dd, J=0.6,4.8 Hz).

Reference Example 75

tert-Butyl 2-(4-pyridyl)ethylcarbamate

4-(2-Aminoethyl)pyridine (4.4 g, 36 mmol) and di-tert-butyl dicarbonate(8.8 g, 40 mmol) were dissolved in tetrahydrofuran (60 ml), and themixture was stirred at 0° C. for 30 minutes and at room temperature for3 hrs. The solvent was evaporated, and the residue was subjected to asilica gel column chromatography. The fraction eluted with ethyl acetatewere collected and concentrated to give the titled compound (6.9 g,81%).

¹H-NMR (CDCl₃) δ: 1.43 (9H, s), 2.80 (2H, t, J=6.9 Hz), 3.40 (2H, m),4.60 (1H, br s), 7.13 (2H, d, J=6.0 Hz), 8.51 (2H, d, J=6.0 Hz).

Reference Example 76

tert-Butyl 2-(2-pyridyl)ethylcarbamate N-oxide

tert-Butyl 2-(2-pyridyl)ethylcarbamate (18.5 g, 83 mmol) and3-chloroperbenzoic acid (77%, 24.5 g, 109 mmol) were dissolved in ethylacetate (200 ml), and the mixture was stirred at room temperature for 15hrs. The solvent was evaporated, and the residue was subjected to asilica gel column chromatography. The fractions eluted withmethanol-ethyl acetate (1:4, v/v) were collected and concentrated togive the titled compound (19.6 g, 99%).

¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 3.16 (2H, t, J=6.4 Hz), 3.53 (2H, m),5.40 (1H, br s), 7.18-7.26 (3H, m), 8.26 (1H, m).

Reference Example 77

tert-Butyl 2-(4-pyridyl)ethylcarbamate N-oxide

tert-Butyl 2-(4-pyridyl)ethylcarbamate (6.9 g, 31 mmol) and3-chloroperbenzoic acid (77%, 9.1 g, 40 mmol) were dissolved in ethylacetate (100 ml), and the mixture was stirred at room temperature for 3hrs. The solvent was evaporated, and the residue was subjected to asilica gel column chromatography. The fractions eluted withmethanol-ethyl acetate (1:3, v/v) were collected and concentrated togive the titled compound (7.4 g, 99%).

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 2.82 (2H, t, J=6.8 Hz), 3.38 (2H, m),4.90 (1H, br s), 7.12 (2H, d, J=6.9 Hz), 8.13 (2H, d, J=6.9 Hz).

Reference Example 78

tert-Butyl 2-(6-cyano-2-pyridyl)ethylcarbamate

tert-Butyl 2-(2-pyridyl)ethylcarbamate N-oxide (6.2 g, 26 mmol) wasdissolved in nitroethane (80 ml), and trimethylsilyl cyanide (7.8 g, 78mmol) and N,N-dimethylcarbamoyl chloride (5.5 g, 51 mmol) were addedthereto. The mixture was stirred at room temperature for 48 hrs. Thesolvent was evaporated, and the residue was subjected to a silica gelcolumn chromatography. The fractions eluted with ethyl acetate-hexane(1:2, v/v) were collected, concentrated and recrystallized fromhexane-ethyl acetate to give the titled compound (5.3 g, 83%).

mp. 79.1-80.3° C.

¹H-NMR (CDCl₃) δ: 1.42 (9H, s) 3.04 (2H, t, J=6.4 Hz), 3.56 (2H, m),4.92 (1H, br s), 7.40 (1H, d, J=7.8 Hz), 7.56 (1H, d, J=7.6 Hz), 7.75(1H, dd, J=7.6, 7.8 Hz).

IR(KBr): 3350, 2976, 2932, 2235, 1697, 1589, 1514, 1452, 1365, 1275,1250 cm⁻¹.

Elemental Analysis for C₁₃H₁₇N₃O₂

Calcd. C, 63.14; H, 6.93; N, 16.99.

Found C, 63.12; H, 6.90; N, 17.02.

Reference Example 79

tert-Butyl 2-(2-cyano-4-pyridyl)ethylcarbamate

tert-Butyl 2-(4-pyridyl)ethylcarbamate N-oxide (7.4 g, 31 mmol) wasdissolved in nitroethane (100 ml), and trimethylsilyl cyanide (9.2 g, 92mmol) and N,N-dimethylcarbamoyl chloride (6.7 g, 62 mmol) were addedthereto. The mixture was stirred at room temperature for 10 hrs. Thesolvent was evaporated, and the residue was subjected to a silica gelcolumn chromatography. The fractions eluted with ethyl acetate-hexane(1:1, v/v) were collected, concentrated and recrystallized fromhexane-ethyl acetate to give the titled compound (6.6 g, 86%)

mp. 70.5-71.2° C.

¹H-NMR (CDCl₃) δ: 1.42 (9H, s) 2.88 (2H, t, J=6.8 Hz), 3.41 (2H, m),4.63 (1H, br s), 7.37 (1H, dd, J=1.3, 4.9 Hz), 7.55 (1H, d, J=1.3 Hz),8.62 (1H, d, J=4.9 Hz).

IR(KBr): 3337, 2976, 2934, 2237, 1697, 1599, 1518, 1365, 1275, 1250,1169 cm⁻¹.

Elemental Analysis for C₁₃H₁₇N₃O₂

Calcd. C, 63.14; H, 6.93; N, 16.99.

Found C, 63.33; H, 6.98; N, 17.05.

Example 217

tert-Butyl 2-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]ethylcarbamate

tert-Butyl 2-(6-cyano-2-pyridyl)ethylcarbamate (2.0 g, 8.1 mmol) andmethyl thiosalicylate (2.0 g, 12 mmol) were dissolved in toluene (10ml), and triethylamine (5.0 ml, 36 mmol) was added thereto. The mixturewas refluxed for 14 hrs. The solvent was evaporated, and the residue wassubjected to a silica gel column chromatography. The fractions elutedwith ethyl acetate-hexane (3:2, v/v) were collected, concentrated andrecrystallized from hexane-tetrahydrofuran to give the titled compound(2.0 g, 64%) as white crystals.

mp. 170.2-170.8° C.

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 3.12 (2H, t, J=6.3 Hz), 3.69 (2H, m),5.27 (1H, br s), 7.40 (1H, d, J=7.6 Hz), 7.61-7.72 (3H, m), 7.83 (1H,m), 8.39 (1H, d, J=7.7 Hz), 8.56 (1H, m).

IR(KBr): 3350, 2976, 2930, 1705, 1660, 1572, 1535, 1300, 1248, 1170, 736cm⁻¹.

Elemental Analysis for C₂₀H₂₁N₃O₃S

Calcd. C, 62.64; H, 5.52; N, 10.96.

Found C, 62.67; H, 5.45; N, 11.08.

Example 218

tert-Butyl 2-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]ethylcarbamate

tert-Butyl 2-(2-cyano-4-pyridyl)ethylcarbamate (3.0 g, 12 mmol) andmethyl thiosalicylate (3.6 g, 21 mmol) were dissolved in toluene (12ml), and triethylamine (6.0 ml, 43 mmol) was added thereto. The mixturewas refluxed for 8 hrs. The solvent was evaporated, and the residue wassubjected to a silica gel column chromatography. The fractions elutedwith ethyl acetate-hexane (2:1, v/v) were collected, concentrated andrecrystallized from hexane-ethanol to give the titled compound (3.3 g,71%) as white crystals.

mp. 159.8-161.0° C.

¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 2.93 (2H, t, J=6.9 Hz), 3.46 (2H, m),4.58 (1H, br s), 7.41 (1H, m), 7.60-7.69 (3H, m), 8.41 (1H, s), 8.55(1H, dd, J=1.4, 8.0 Hz), 8.64 (1H, d, J=4.9 Hz).

IR(KBr): 3350, 2976, 2930, 1705, 1660, 1572, 1535, 1300, 1248, 1170, 736cm⁻¹.

Elemental Analysis for C₂₀H₂₁N₃O₃S

Calcd. C, 62.64; H, 5.52; N, 10.96.

Found C, 62.67; H, 5.62; N, 10.88.

Example 219

tert-Butyl 2-[2-(7-chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]ethylcarbamate

tert-Butyl 2-(2-cyano-4-pyridyl)ethylcarbamate (1.5 g, 6.0 mmol) and4-chlorothiosalicylic acid (2.3 g, 12.1 mmol) were dissolved in pyridine(10 ml), and the mixture was refluxed for 18 hrs. The solvent wasevaporated, and the residue was subjected to a silica gel columnchromatography. The fractions eluted with hexane-ethyl acetate (1:1,v/v) were collected, concentrated and recrystallized fromhexane-tetrahydrofuran to give the titled compound (0.48 g, 19%) aswhite crystals.

mp. 168.2-169.2° C.

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 2.94 (2H, t, J=6.9 Hz), 3.46 (2H, m),4.60 (1H, br s), 7.42 (1H, d, J=4.0 Hz), 7.56-7.60 (2H, m), 8.38 (1H,s), 8.48 (1H, d, J=8.3 Hz), 8.64 (1H, d, J=4.9 Hz).

IR(KBr): 3377, 2980, 1685, 1655, 1585, 1560, 1531, 1381, 1284, 1165, 729cm⁻¹.

Elemental Analysis for C₂₀H₂₀N₃O₃SCl

Calcd. C, 57.48; H, 4.82; N, 10.05.

Found C, 57.67; H, 4.88; N, 9.86.

Example 220

2-[6-(2-Aminoethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-onetrifluoroacetic acid salt

tert-Butyl 2-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]ethylcarbamate (0.35 g, 0.91 mmol) was dissolved in trifluoroacetic acid (4 ml),and the mixture was stirred at room temperature for 2 hrs. The solventwas evaporated, and the residue was recrystallized frommethanol-diisopropyl ether to give the titled compound (0.33 g, 91%) aswhite crystals.

mp. 206.2-207.1° C.

¹H-NMR (DMSO-d₆) δ: 3.22 (2H, t, J=7.0 Hz), 3.37 (2H, t, J=7.0 Hz),7.70-7.77 (2H, m), 7.82-7.91 (2H, m), 7.99 (3H, br s), 8.08 (1H, m),8.25 (1H, d, J=7.8 Hz), 8.37 (1H, d, J=7.9 Hz).

IR(KBr): 3130, 1676, 1662, 1574, 1541, 1483, 1203, 1184, 1120, 817, 798cm⁻¹.

Elemental Analysis for C₁₇H₁₄N₃O₃SF₃

Calcd. C, 51.38; H, 3.55; N, 10.57.

Found C, 51.41; H, 3.80; N, 10.62.

Example 221

2-[4-(2-Aminoethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-onetrifluoroacetic acid salt

tert-Butyl 2-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]ethylcarbamate (0.82 g, 2.1 mmol) was dissolved in trifluoroacetic acid (10 ml),and the mixture was stirred at room temperature for 2 hrs. The solventwas evaporated, and the residue was recrystallized frommethanol-diisopropyl ether to give the titled compound (0.75 g, 89%) aswhite crystals.

mp. 209.0-210.7° C.

¹H-NMR (DMSO-d₆) δ: 3.06 (2H, t, J=7.2 Hz), 3.21 (2H, m) 7.68-7.77 (2H,m), 7.82-7.95 (5H, m), 8.31 (1H, s), 8.37 (1H, d, J=7.8 Hz), 8.76 (1H,d, J=4.6 Hz).

IR(KBr): 2990, 1678, 1635, 1521, 1203, 1174, 1145, 833 cm⁻¹.

Elemental Analysis for C₁₇H₁₄N₃O₃SF₃

Calcd. C, 51.38; H, 3.55; N, 10.57.

Found C, 51.28; H, 3.48; N, 10.64.

Example 222

2-[4-(2-Aminoethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one hydrochloridesalt

tert-Butyl 2-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]ethylcarbamate (0.40 g, 1.0 mmol) was dissolved in ethyl acetate (20 ml), and 4 Nhydrochloric acid in ethyl acetate (2 ml) was added thereto dropwise at0° C. The mixture was stirred at the same temperature for 1 hr. Theprecipitates were collected by filtration and recrystallized fromdiisopropyl ether-methanol to give the titled compound (0.04 g, 12%) aswhite crystals.

mp. 238° C. (decomposed)

¹H-NMR (DMSO-d₆) δ: 3.12 (2H, m), 3.17 (2H, m), 7.71 (1H, d, J=4.9 Hz),7.76 (1H, d, J=7.8 Hz), 7.85 (1H, m), 7.93 (1H, d, J=8.0 Hz), 8.10 (3H,br s), 8.30 (1H, s), 8.37 (1H, d, J=7.8 Hz), 8.76 (1H, d, J=4.9 Hz).

IR(KBr): 2889, 2739, 2640, 1633, 1518, 1304, 1099 cm⁻¹.

Elemental Analysis for C₁₅H₁₄N₃OSCl·0.25H₂O

Calcd. C, 55.55; H, 4.51; N, 12.96.

Found C, 55.71; H, 4.43; N, 12.91.

Example 223

2-[4-(2-Aminoethyl)-2-pyridyl]-7-chloro-4H-1,3-benzothiazin e-4-onetrifluoroacetic acid salt

tert-Butyl 2-[2-(7-chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]ethylcarbamate (0.36 g, 0.86 mmol) was dissolved in trifluoroacetic acid(10 ml), and the mixture was stirred at room temperature for 3 hrs. Thesolvent was evaporated, and the residue was recrystallized frommethanol-diisopropyl ether to give the titled compound (0.33 g, 89%) aswhite crystals.

mp. 212° C. (decomposed)

¹H-NMR (DMSO-d₆) δ: 3.06 (2H, t, J=7.2 Hz), 3.20 (2H, m), 7.70 (1H, dd,J=1.5, 4.9 Hz), 7.78 (1H, dd, J=2.0, 8.5 Hz), 7.87 (3H, br s), 8.18 (1H,d, J=2.0 Hz), 8.30 (1H, d, J=1.5 Hz), 8.34 (1H, d, J=8.5 Hz), 8.76 (1H,d, J=4.9 Hz).

IR(KBr): 3047, 1693, 1635, 1560, 1520, 1203, 1165, 1138 cm⁻¹.

Elemental Analysis for C₁₇H₁₃N₃O₃SF₃Cl

Calcd. C, 47.28; H, 3.03; N, 9.73.

Found C, 47.27; H, 3.23; N, 9.79.

Example 224

N-[2-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]ethyl]be nzamide

2-[6-(2-Aminoethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-onetrifluoroacetic acid salt (0.53 g, 1.3 mmol) was dissolved inN,N-dimethylacetamide (10 ml), and benzoyl chloride (0.38 g, 2.7 mmol)and potassium carbonate (0.18 g, 1.3 mmol) were added thereto. Thereaction mixture was stirred at 60° C. for 4 hrs, combined with ethylacetate and water. The organic layer was successively washed withsaturated aqueous sodium hydrogen carbonate solution and saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated, and the residue was subjected to a silica gel columnchromatography. The fractions eluted with methanol-ethyl acetate (1:20,v/v) were collected, concentrated and recrystallized from hexane-ethanolto give the titled compound (0.13 g, 26%) as white crystals.

mp. 201.7-202.6° C.

¹H-NMR (CDCl₃) δ: 3.27 (2H, t, J=6.0H), 4.04 (2H, t, J=6.0 Hz),7.37-7.47 (6H, m), 7.60-7.70 (2H, m), 7.81-7.85 (3H, m), 8.40 (1H, d,J=7.4 Hz), 8.55 (1H, m).

IR(KBr): 3325, 1643, 1572, 1529, 1439, 1302, 736 cm⁻¹.

Elemental Analysis for C₂₂H₁₇N₃O₂S

Calcd. C, 68.20; H, 4.42; N, 10.85.

Found C, 68.40; H, 4.35; N, 10.78.

Example 225

N-[2-[2-(4-Oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]ethyl]be nzamide

2-[4-(2-Aminoethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-onetrifluoroacetic acid salt (0.50 g, 1.2 mmol) was dissolved inN,N-dimethylacetamide (10 ml), and benzoyl chloride (0.36 g, 2.6 mmol)and potassium carbonate (0.17 g, 1.2 mmol) were added thereto. Thereaction mixture was stirred at 60° C. for 5 hrs, combined with ethylacetate and water. The organic layer was successively washed withsaturated aqueous sodium hydrogen carbonate solution and saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated, and the residue was subjected to a silica gel columnchromatography. The fractions eluted with methanol-ethyl acetate (1:20,v/v) were collected, concentrated and recrystallized fromhexane-chloroform to give the titled compound (0.17 g, 36%) as whitecrystals.

mp. 216.8-219.3° C.

¹H-NMR (CDCl₃) δ: 3.07 (2H, t, J=6.9H), 3.80 (2H, m), 6.54 (1H, m),7.41-7.48 (4H, m), 7.62-7.77 (5H, m), 8.41 (1H, s), 8.52 (1H, m), (1H,d, J=4.9H).

IR(KBr): 3287, 3061, 1657, 1643, 1572, 1531, 1304, 1282, 742 cm⁻¹.

Elemental Analysis for C₂₂H₁₇N₃O₂S

Calcd. C, 68.20; H, 4.42; N, 10.85.

Found C, 67.91; H, 4.33; N, 10.81.

Example 226

N-[2-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyrizyl]ethyl]ac etamide

2-[6-(2-Aminoethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-onetrifluoroacetic acid salt (0.58 g, 1.4 mmol) was dissolved inN,N-dimethylacetamide (10 ml), and acetyl chloride (0.38 g, 4.8 mmol)and potassium carbonate (0.20 g, 1.4 mmol) were added thereto. Thereaction mixture was stirred at 60° C. for 8 hrs, combined with ethylacetate and water. The organic layer was washed with saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporated,and the residue was subjected to a silica gel column chromatography. Thefractions eluted with methanol-ethyl acetate (1:8, v/v) were collected,concentrated and recrystallized from diisopropyl ether-methanol to givethe titled compound (0.15 g, 31%) as pale yellow crystals.

mp. 206.7-207.9° C.

¹H-NMR (CDCl₃) δ: 2.04 (3H, s), 3.14 (2H, t, J=6.1 Hz), 3.83 (2H, m),6.53 (1H, br s), 7.41 (1H, d, J=7.6 Hz), 7.58-7.70 (3H, m), 7.83 (1H,m), 8.37 (1H, d, J=7.7 Hz), 8.55 (1H, dd, J=1.5, 7.7 Hz).

IR(KBr): 3325, 1643, 1572, 1529, 1439, 1302, 736 cm⁻¹.

Elemental Analysis for C₁₇H₁₅N₃O₂S

Calcd. C, 62.75; H, 4.65; N, 12.91.

Found C, 62.63; H, 4.63; N, 12.94.

Example 227

N-[2-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]ethyl]-N ′-phenylurea

A mixture of 2-[6-(2-aminoethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-onetrifluoroacetic acid salt (0.40 g, 1.0 mmol), potassium carbonate (0.41g, 3.0 mmol) and acetonitrile (15 ml) was stirred at room temperaturefor 20 minutes. Successively phenyl isocyanate (0.47 g, 4.0 mmol) wasadded to the mixture, and the mixture was refluxed for 4 hrs. Aftercooling, the precipitates were collected by filtration and dissolved inchlorobenzene and water. The organic layer was dried over magnesiumsulfate. The solvent was evaporated, and the residue was recrystallizedfrom hexane-chlorobenzene to give the titled compound (0.07 g, 17%) aspale yellow crystals.

mp. 234.8-236.4° C.

¹H-NMR (DMSO-d₆) δ: 3.08 (2H, t, J=6.6H), 3.61 (2H, m), 6.21 (1H, m),6.87 (1H, m), 7.19 (2H, m), 7.36 (2H, d, J=7.7 Hz), 7.66 (1H, d, J=7.6Hz), 7.73 (1H, m), 7.81-7.88 (2H, m), 8.04 (1H, m), 8.22 (1H, d, J=7.7Hz), 8.36 (1H, d, J=7.6 Hz), 8.46 (1H, s).

IR(KBr): 3422, 3325, 2943, 1687, 1641, 1597, 1570, 1541, 1496, 1440,1311 cm⁻¹.

Elemental Analysis for C₂₂H₁₈N₄O₂S 0.5H₂O

Calcd. C, 64.22; H, 4.65; N, 13.62.

Found C, 64.27; H, 4.40; N, 13.61.

Example 228

N-Ethyl-N′-[2-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl ]ethyl]urea

A mixture of 2-[6-(2-aminoethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-onetrifluoroacetic acid salt (0.45 g, 1.1 mmol), potassium carbonate (0.47g, 3.4 mmol) and acetonitrile (20 ml) was stirred at room temperaturefor 20 minutes. Successively ethyl isocyanate (0.36 g, 5.1 mmol) wasadded to the mixture, and the mixture was refluxed for 3 hrs. Aftercooling, the precipitates were collected by filtration, dissolved inchloroform and subjected to a silica gel column chromatography. Thefractions eluted with chloroform-ethanol (15:1, v/v) were collected,concentrated and recrystallized from chloroform-hexane to give thetitled compound (0.25 g, 63%) as white crystals.

mp. 240.3-242.4° C.

¹H-NMR (DMSO-d₆) δ: 0.96 (3H, t, J=7.1H), 2.95-3.04 (4H, m), 3.49 (2H,m), 5.83 (1H, t, J=5.4 Hz), 5.88 (1H, t, J=5.6 Hz), 7.61 (1H, d, J=7.5Hz), 7.75 (1H, m), 7.85 (1H, m), 7.95 (1H, d, J=7.6 Hz), 8.02 (1H, m),8.20 (1H, d, J=7.6 Hz), 8.36 (1H, dd, J=0.8, 7.8 Hz).

IR(KBr): 3319, 1660, 1622, 1572, 1539, 1302, 1095, 744 cm⁻¹.

Elemental Analysis for C₁₈H₁₈N₄O₂S

Calcd. C, 61.00; H, 5.12; N, 15.81.

Found C, 60.85; H, 5.11; N, 15.81.

Example 229

N,N-Dimethyl-N′-[2-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]ethyl]urea

A mixture of 2-[6-(2-aminoethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-onetrifluoroacetic acid salt (0.45 g, 1.1 mmol), potassium carbonate (0.46g, 3.3 mmol) and acetonitrile (20 ml) was stirred at room temperaturefor 20 minutes. Successively N,N-dimethylcarbamoyl chloride (0.47 g, 4.3mmol) was added to the mixture, and the mixture was stirred at roomtemperature for 3 hrs. The precipitates were filtered, and the filtratewas concentrated. The residue was subjected to a silica gel columnchromatography. The fractions eluted with chloroform-ethanol (20:1, v/v)were collected, concentrated and recrystallized from chloroform-hexaneto give the titled compound (0.31 g, 77%) as white crystals.

mp. 190.2-191.0° C.

¹H-NMR (CDCl₃) δ: 2.89 (6H, s), 3.16 (2H, t, J=6.2 Hz), 3.81 (2H, m),5.17 (1H, m), 7.43 (1H, d, J=7.6 Hz), 7.59-7.71 (3H, m), 7.84 (1H, m),8.38 (1H, d, J=7.8 Hz), 8.54 (1H, m).

IR(KBr): 3352, 2928, 1655, 1637, 1570, 1533, 1439, 1300, 1232, 1097, 736cm⁻¹.

Elemental Analysis for C₁₈H₁₈N₄O₂S·0.25H₂O

Calcd. C, 60.23; H, 5.20; N, 15.61.

Found C, 60.36; H, 5.15; N, 15.56.

Example 230

N,N-Diethyl-N′-[2-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]ethyl]urea

A mixture of 2-[6-(2-aminoethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-onetrifluoroacetic acid salt (0.40 g, 1.0 mmol), potassium carbonate (0.41g, 3.0 mmol) and acetonitrile (20 ml) was stirred at room temperaturefor 20 minutes. Successively N,N-diethylcarbamoyl chloride (0.54 g, 4.0mmol) was added to the mixture, and the mixture was stirred at roomtemperature for 4 hrs. The precipitates were filtered, and the filtratewas concentrated. The residue was subjected to a silica gel columnchromatography. The fractions eluted with chloroform-ethanol (30:1, v/v)were collected, concentrated and recrystallized from ethanol-hexane togive the titled compound (0.12 g, 31%) as white crystals.

mp. 174.9-175.6° C.

¹H-NMR (CDCl₃) δ: 1.06 (6H, t, J=7.1 Hz), 3.15-3.26 (6H, m), 3.82 (2H,m), 5.06 (1H, m), 7.42 (1H, d, J=7.7 Hz), 7.58-7.70 (3H, m), 7.83 (1H,m), 8.38 (1H, d, J=7.7 Hz), 8.56 (1H, m).

IR(KBr): 3358, 2972, 2930, 1658, 1643, 1572, 1531, 1439, 1282, 1097, 736cm⁻¹.

Elemental Analysis for C₂₀H₂₂N₄O₂S

Calcd. C, 62.80; H, 5.80; N, 14.65.

Found C, 62.88; H, 5.73; N, 14.64.

Reference Example 80

tert-Butyl 2-pyridylcarbamate

2-Aminopyridine (6.0 g, 63.7 mmol) and di-tert-butyl dicarbonate (14.4g, 65.9 mol) were dissolved in tetrahydrofuran (150 ml), and the mixturewas refluxed for 12 hrs. After cooling, the precipitates were filtered,and the filtrate was concentrated. The residue was subjected to a silicagel column chromatography. The fractions eluted with hexane-ethylacetate (15:1, v/v) were collected and concentrated to give the titledcompound (7.5 g, 60%).

¹H-NMR (CDCl₃) δ: 1.54 (9H, s), 6.94 (1H, m), 7.65 (1H, m), 7.96 (1H, d,J=8.4 Hz), 8.29 (1H, d, J=4.6 Hz), 8.70 (1H, br s).

Reference Example 81

tert-Butyl 2-pyridylcarbamate N-oxide

tert-Butyl 2-pyridylcarbamate (7.4 g, 38 mmol) and 3-chloroperbenzoicacid (77%, 11.2 g, 50 mmol) were dissolved in ethyl acetate (100 ml),and the mixture was stirred at room temperature for 20 hrs. The solventwas evaporated, and the residue was subjected to a silica gel columnchromatography. The fractions eluted with methanol-ethyl acetate (1:20,v/v) were collected and concentrated to give the titled compound (7.6 g,95%).

¹H-NMR (CDCl₃) δ: 1.54 (9H, s), 6.91 (1H, m), 7.29 (1H, m), 8.15 (1H,dd, J=1.6, 8.5 Hz), 8.20 (1H, m), 9.30 (1H, br s)

Reference Example 82

N′-(6-Cyano-2-pyridyl)-N,N-dimethylurea

tert-Butyl 2-pyridylcarbamate N-oxide (7.6 g, 36 mmol) was dissolved innitroethane (100 ml), and trimethylsilyl cyanide (14.5 g, 146 mmol) andN,N-dimethylcarbamoyl chloride (15.8 g, 147 mmol) were added thereto.The mixture was stirred at room temperature for 3 days and at 50° C. for24 hrs. The solvent was evaporated, and the residue was subjected to asilica gel column chromatography. The fractions eluted with ethylacetate-hexane (1:1, v/v) were collected and concentrated. The residuewas crystallized from hexane to give tert-butyl 6-cyano-2-pyridyl[(dimethylamino)carbonyl]carbamate (3.3 g) Furthermore, this compound(3.3 g) was dissolved in trifluoroacetic acid (20 ml), and the mixturewas stirred at 0° C. for 3 hrs. The solvent was evaporated, and theresidue was subjected to a silica gel. The fractions eluted withhexane-ethyl acetate (1:1, v/v) were collected, concentrated andrecrystallized from hexane-ethyl acetate to give the titled compound(1.0 g, 15%).

mp. 124.6-124.8° C.

¹H-NMR (CDCl₃) δ: 3.06 (6H, s), 7.31 (1H, br s), 7.32 (1H, d, J=7.4 Hz),7.74 (1H, dd, J=7.4, 8.6 Hz), 8.33 (1H, d, J=8.6 Hz).

IR(KBr): 3408, 2941, 2235, 1666, 1574, 1529, 1452, 1400, 1307, 1174, 983cm⁻¹.

Elemental Analysis for C₉H₁₀N₄O

Calcd. C, 56.83; H, 5.30; N, 29.46.

Found C, 56.82; H, 5.37; N, 29.60.

Example 231

N,N-Dimethyl-N′-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyrid yl]urea

N′-(6-Cyano-2-pyridyl)-N,N-dimethylurea (0.72 g, 3.8 mmol) and methylthiosalicylate (0.89 g, 5.2 mmol) were dissolved in toluene (4 ml), andtriethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture wasrefluxed for 8 hrs. After cooling, the precipitates were collected andrecrystallized from diisopropyl ether-methanol to give the titledcompound (0.62 g, 50%) as white crystals.

mp. 230.1-230.3° C.

¹H-NMR (CDCl₃) δ: 3.13 (6H, s), 7.28 (1H, s), 7.52 (1H, d, J=7.2 Hz),7.59-7.64 (2H, m), 7.81 (1H, m), 8.14 (1H, d, J=7.5 Hz), 8.27 (1H, d,J=8.3 Hz), 8.52 (1H, m).

IR(KBr): 3485, 1651, 1579, 1529, 1456, 1404, 1300, 989, 808, 738 cm⁻¹.

Elemental Analysis for C₁₆H₁₄N₄O₂S

Calcd. C, 58.88; H, 4.32; N, 17.17.

Found C, 58.74; H, 4.08; N, 17.06.

Example 232

tert-Butyl 6-(8-methyl-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridinecarboxylate

tert-Butyl 6-cyano-2-pyridinecarboxylate (3.2 g, 15 mmol) and3-methylthiosalicylic acid (4.7 g, 28 mmol) were dissolved in pyridine(40 ml), and the mixture was refluxed for 16 hrs. The solvent wasevaporated, and the residue was subjected to a silica gel columnchromatography. The fractions eluted with hexane-tetrahydrofuran (2:1,v/v) were collected, concentrated and recrystallized fromhexane-tetrahydrofuran to give the titled compound (3.1 g, 56%) as paleyellow crystals.

mp. 204.3-204.7° C.

¹H-NMR (CDCl₃) δ: 1.69 (9H, s), 2.60 (3H, s), 7.53-7.55 (2H, m), 8.03(1H, dd, J=7.8, 7.8 Hz), 8.25 (1H, dd, J=0.9, 7.8 Hz), 8.44 (1H, m),8.69 (1H, dd, J=0.9, 7.8 Hz).

IR(KBr): 2974, 2932, 1712, 1658, 1579, 1541, 1327, 1311, 1182, 1153, 771cm⁻¹.

Elemental Analysis for C₁₉H₁₈N₂O₃S

Calcd. C, 64.39; H, 5.12; N, 7.90.

Found C, 64.29; H, 4.87; N, 7.78.

Example 233

6-(8-Methyl-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridinecarbo xylic acid

tert-Butyl 6-(8-methyl-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridinecarboxylate (0.50 g, 1.4 mmol) was dissolved in trifluoroacetic acid (5 ml),and the mixture was stirred at 0° C. for 4 hrs. The solvent wasevaporated, and the residue was crystallized from diethyl ether to givethe titled compound (0.39 g, 94%) as pale yellow crystals.

mp. 260.5-260.8° C.

¹H-NMR (DMSO-d₆) δ: 2.55 (3H, s), 7.62 (1H, m), 7.73 (1H, d, J=7.1 Hz),8.21-8.34 (3H, m), 8.54 (1H, m), 13.70 (1H, br s).

IR(KBr): 3067, 1697, 1672, 1543, 1471, 1307, 1099, 773 cm⁻¹.

Elemental Analysis for C₁₅H₁₀N₂O₃S

Calcd. C, 60.39; H, 3.38; N, 9.39.

Found C, 60.10; H, 3.32; N, 9.27.

Example 234

tert-Butyl6-[[[6-(8-methyl-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]carbonyl]amino]hexylcarbamate

6-(8-Methyl-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridin ecarboxylic acid(1.5 g, 5.0 mmol) was dissolved in DMF (15 ml) andN-(tert-butoxycarbonyl)-1,6-diaminohexane (2.1 g, 10.0 mmol), WSC (3.0g, 15.5 mmol) and HOBt (2.0 g, 14.9 mmol) were added thereto. Thereaction mixture was stirred at 80° C. for 10 hrs and combined withethyl acetate and water. The organic layer was washed with saturatedbrine and dried over magnesium sulfate. The solvent was evaporated andthe residue was subjected to a silica gel column chromatography. Thefractions eluted with ethyl acetate-hexane (4:1, v/v) were collected,concentrated and recrystallized from hexane-tetrahydrofuran to give thetitled compound (1.1 g, 45%) as white crystals.

mp. 170.7-171.5° C.

¹H-NMR (DMSO-d₆) δ: 1.43 (9H, s), 1.43-1.55 (6H, m), 1.74 (2H, m), 2.60(3H, s), 3.13 (2H, m), 3.57 (2H, m), 4.52 (1H, br s), 7.55 (1H, m), 7.56(1H, s), 7.98 (1H, m), 8.08 (1H, m), 8.41-8.45 (2H, m), 8.66 (1H, dd,J=0.9, 7.8 Hz).

IR(KBr): 3350, 2932, 2858, 1680, 1666, 1537, 1448, 1307, 1271, 1250,1172 cm⁻¹.

Elemental Analysis for C₂₆H₃₂N₄O₄S

Calcd. C, 62.88; H, 6.49; N, 11.28.

Found C, 62.78; H, 6.51; N, 11.09.

Example 235

N-(6-Aminohexyl)-6-(8-methyl-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridinecarboxamide hydrochloride salt

tert-Butyl 6-[[[6-(8-methyl-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]carbonyl]amino]hexylcarbamate (0.30 g, 0.60 mmol) was dissolved indioxane (10 ml), and 4 N hydrochloric acid in dioxane (1.0 ml. 4.00 mol)was added thereto. The reaction mixture was stirred at room temperaturefor 24 hrs. The precipitates were collected by filtration andrecrystallized from diisopropyl ether-methanol to give the titledcompound (0.05 g, 20%) as pale yellow crystals.

mp. 240° C.

¹H-NMR (CDCl₃) δ: 1.40 (4H, m), 1.57-1.64 (4H, m), 2.59 (3H, s), 2.76(2H, m), 3.43 (2H, m), 7.64 (1H, m), 7.74 (1H, d, J=7.3 Hz), 7.96 (3H,br s), 8.22-8.31 (3H, m), 8.49 (1H, m), 8.60 (1H, m).

IR(KBr): 3337, 2858, 1651, 1529, 1317, 758 cm⁻¹.

Elemental Analysis for C₂₁H₂₅N₄O₂SCl·0.25H₂O

Calcd. C, 57.66; H, 5.88; N, 12.81.

Found C, 57.61; H, 5.58; N, 12.75.

Reference Example 83

2-(2-Pyridylmethyl)-1H-isoindole-1,3(2H)-dione

2-Aminomethylpyridine (4.0 g, 37 mmol) and phthalic anhydride (5.5 g, 37mmol) were dissolved in toluene (100 ml), and triethylamine (3.7 g, 36mmol) was added thereto. The mixture was refluxed for 3 hrs. The solventwas evaporated, and the residue was recrystallized from hexane-ethanolto give the titled compound (7.6 g, 86%).

¹H-NMR (CDCl₃) δ: 5.01 (2H, s), 7.16 (1H, dd, J=4.9, 7.4 Hz), 7.27 (1H,d, J=8.4 Hz), 7.63 (1H, m), 7.72 (2H, m), 7.88 (2H, m), 8.52 (1H, d,J=4.6 Hz).

Reference Example 84

2-(2-Pyridylmethyl)-1H-isoindole-1,3(2H)-dione N-oxide

2-(2-Pyridylmethyl)-1H-isoindole-1,3(2H)-dione (7.5 g, 32 mmol) and3-chloroperbenzoic acid (77%, 14.3 g, 64 mmol) were dissolved inchloroform (250 ml), and the mixture was stirred at room temperature for20 hrs. The solvent was evaporated, and the residue was washed withethyl acetate to give the titled compound (8.0 g, 99%) as whitecrystals.

¹H-NMR (CDCl₃) δ: 5.16 (2H, s), 7.15 (1H, m), 7.24-7.26 (2H, m) 7.77(2H, m), 7.90 (2H, m), 8.33 (1H, m).

Reference Example 85

6-[(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-pyridinecarbonitrile

2-(2-Pyridylmethyl)-1H-isoindole-1,3(2H)-dione N-oxide (8.0 g, 31 mmol)was dissolved in mixed solvent of nitroethane (80 ml) and chloroform(150 ml), and trimethylsilyl cyanide (9.3 g, 94 mmol) andN,N-dimethylcarbamoyl chloride (6.8 g, 63 mmol) were added thereto. Themixture was stirred at room temperature for 4 hrs and at 60° C. for 24hrs. The solvent was evaporated, and the residue was subjected to asilica gel column chromatography. The fractions eluted with hexane-ethylacetate (2:1, v/v) were collected, concentrated and recrystallized fromhexane-tetrahydrofuran to give the titled compound (1.8 g, 22%) as whitecrystals.

mp. 204.7-204.9° C.

¹H-NMR (CDCl₃) δ: 5.05 (2H, s) 7.50 (1H, d, J=8.0 Hz), 7.59 (1H, d,J=7.6 Hz), 7.74-7.82 (3H, m), 7.87-7.93 (2H, m).

IR(KBr): 3080, 2245, 1776, 1713, 1421, 1396, 1323, 1111, 950 cm⁻¹

Elemental Analysis for C₁₅H₉N₃O₂

Calcd. C, 68.44; H, 3.45; N, 15.96.

Found C, 68.43; H, 3.40; N, 15.88.

Example 236

2-[[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methyl]-1H-isoindole-1,3(2H)-dione

6-[(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-pyridinecarbonitrile(1.25 g, 4.7 mmol) and methyl thiosalicylate (1.59 g, 9.4 mmol) weredissolved in toluene (10 ml), and triethylamine (5.0 ml, 35.8 mmol) wasadded thereto. The reaction mixture was refluxed for 15 hrs. Aftercooling, the precipitates were collected by filtration andrecrystallized from hexane-chloroform to give the titled compound (1.48g, 78%) as white crystals.

mp. 280.4-281.1° C.

¹H-NMR (CDCl₃) δ: 5.16 (2H, s), 7.24 (1H, dd, J=1.3, 7.2 Hz), 7.52-7.63(3H, m), 7.81-7.84 (2H, m), 7.88 (1H, m), 7.94-7.99 (2H, m), 8.39 (1H,d, J=7.8 Hz), 8.48 (1H, dd, J=1.5, 6.8 Hz).

IR(KBr): 3026, 1766, 1709, 1658, 1572, 1531, 1425, 1394, 1296, 949, 723cm⁻¹.

Elemental Analysis for C₂₂H₁₃N₃O₃S

Calcd. C, 66.15; H, 3.28; N, 10.52.

Found C, 66.17; H, 3.20; N, 10.51.

Example 237

N-Butyl-4-oxo-2-(2-pyridyl)-4H-1,3-benzothiazine-7-carboxam ide

N,N′-carbonyldiimidazole (570 mg, 3.5 mmol) was added to a mixture of4-oxo-2-(2-pyridyl)-4H-1,3-benzothiazine-7-carboxylic acid (800 mg, 2.8mmol) and tetrahydrofuran (20 ml), and the mixture was stirred at 60° C.for 2 hrs. Successively, butylamine (410 mg, 5.6 mmol) was added to thereaction mixture, and the mixture was stirred at 60° C. for 30 minutes.The solvent was evaporated, and the residue was subjected to a silicagel column chromatography. The fractions eluted with hexane-ethylacetate (1:3, v/v) were collected, concentrated and recrystallized fromhexane-tetrahydrofuran to give the titled compound (478 mg, 50%) aswhite crystals.

mp. 193.5-194.2° C.

¹H-NMR (CDCl₃) δ: 0.98 (3H, t, J=7.3 Hz), 1.46 (2H, m), 1.64 (2H, m),3.50 (2H, m), 6.47 (1H, br s), 7.55 (1H, m), 7.86-7.93 (2H, m), 8.07(1H, d, J=1.4 Hz), 8.50 (1H, d, J=7.8 Hz), 8.55 (1H, d, J=8.2 Hz), 8.73(1H, d, J=3.9 Hz).

IR(KBr): 3358, 2961, 2932, 2872, 1658, 1643, 1556, 1518, 1467, 1307,1284 cm⁻¹.

Elemental Analysis for C₁₈H₁₇N₃O₂S

Calcd. C, 63.70; H, 5.05; N, 12.38.

Found C, 63.69; H, 4.97; N, 12.50.

Example 238

2-(2-Pyridyl)-7-(1-pyrrolidinylcarbonyl)-4H-1,3-benzothiazi ne-4-one

N,N′-carbonyldiimidazole (445 mg, 2.7 mmol) was added to a mixture of4-oxo-2-(2-pyridyl)-4H-1,3-benzothiazine-7-carboxylic acid (600 mg, 2.1mmol) and tetrahydrofuran (20 ml), and the mixture was stirred at 60° C.for 2 hrs. Successively, pyrrolidine (300 mg, 4.2 mmol) was added to thereaction mixture, and the mixture was stirred at 60° C. for 1 hr. Thesolvent was evaporated, and the residue was subjected to a silica gelcolumn chromatography. The fractions eluted with ethyl acetate werecollected, concentrated and recrystallized from hexane-tetrahydrofuranto give the titled compound (83 mg, 11%) as white crystals.

mp. 173.6-174.2° C.

¹H-NMR (CDCl₃) δ: 1.94 (2H, m), 1.99 (2H, m), 3.43 (2H, t, J=6.4 Hz),3.69 (2H, t, J=6.7 Hz), 7.56 (1H, m), 7.72 (1H, dd, J=1.5, 8.1 Hz), 7.76(1H, d, J=1.1 Hz), 7.92 (1H, m), 8.53-8.58 (2H, m), 8.75 (1H, d, J=4.5Hz).

IR(KBr): 2972, 2876, 1660, 1626, 1560, 1529, 1433, 1302, 1278, 1236, 794cm⁻¹.

Elemental Analysis for C₁₈H₁₅N₃O₂S 0.5H₂O

Calcd. C, 62.41; H, 4.66; N, 12.13.

Found C, 63.69; H, 4.97; N, 12.14.

Example 239

N-Cyclopropyl-4-oxo-2-(2-pyridyl)-4H-1,3-benzothiazine-7-ca rboxamide

N,N′-carbonyldiimidazole (520 mg, 3.2 mmol) was added to a mixture of4-oxo-2-(2-pyridyl)-4H-1,3-benzothiazine-7-carboxylic acid (700 mg, 2.4mmol) and tetrahydrofuran (20 ml), and the mixture was stirred at 60° C.for 2 hrs. Successively, cyclopropylamine (700 mg, 12.2 mmol) was addedto the reaction mixture, and the mixture was stirred at 60° C. for 1 hr.The solvent was evaporated, and the residue was subjected to a silicagel column chromatography. The fractions eluted with ethyl acetate werecollected, concentrated and recrystallized from diisopropylether-methanol to give the titled compound (45 mg, 5%) as pale yellowcrystals.

mp. 272.1-274.1° C.

¹H-NMR (DMSO-d₆+CDCl₃) δ: 0.71 (2H, m), 0.83 (2H, m), 2.96 (1H, m), 7.60(1H, m), 7.95 (1H, m), 8.08 (1H, dd, J=1.5, 8.3 Hz), 8.20 (1H, d, J=1.5Hz), 8.48-8.53 (2H, m), 8.76 (1H, d, J=4.2 Hz), 8.28 (1H, br s).

IR(KBr): 3354, 3331, 3072, 1655, 1635, 1560, 1520, 1471, 1298, 1286,1109 cm⁻¹.

Elemental Analysis for C₁₇H₁₃N₃O₂S

Calcd. C, 63.14; H, 4.05; N, 12.99.

Found C, 62.93; H, 3.99; N, 13.00.

Example 240

7-(4-Morpholinocarbonyl)-2-(2-pyridyl)-4H-1,3-benzothiazine -4-one

N,N′-carbonyldiimidazole (710 mg, 4.4 mmol) was added to a mixture of4-oxo-2-(2-pyridyl)-4H-1,3-benzothiazine-7-carboxylic acid (750 mg, 2.6mmol) and tetrahydrofuran (20 ml), and the mixture was stirred at 60° C.for 2 hrs. Successively, morpholine (700 mg, 8.0 mmol) was added to thereaction mixture, and the mixture was stirred at 60° C. for 1 hr. Thesolvent was evaporated, and the residue was subjected to a silica gelcolumn chromatography. The fractions eluted with methanol-ethyl acetate(1:20, v/v) were collected, concentrated and recrystallized fromhexane-tetrahydrofuran to give the titled compound (436 mg, 47%) aswhite crystals.

mp. 217.6-218.8° C.

¹H-NMR (CDCl₃) δ: 3.45 (2H, m), 3.68-3.81 (6H, m), 7.55-7.67 (3H, m),7.93 (1H, m), 8.53 (1H, d, J=7.8 Hz), 8.57 (1H, d, J=8.3 Hz), 8.75 (1H,s).

IR(KBr): 3528, 2972, 2912, 2858, 1660, 1639, 1560, 1529, 1435, 1280,1113 cm⁻¹.

Elemental Analysis for C₁₈H₁₅N₃O₃S·0.25H₂O

Calcd. C, 60.41; H, 4.37; N, 11.74.

Found C, 60.42; H, 4.10; N, 11.79.

Example 241

7-Bromo-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one

2-Cyanopyridine (0.29 g, 2.8 mmol) and 4-bromothiosalicylic acid (0.8 g,3.4 mmol) were dissolved in pyridine (6 ml), and the mixture wasrefluxed for 8 hrs. The solvent was evaporated, and the residue wassubjected to silica gel column chromatography. The fractions eluted withchloroform-ethyl acetate (5:1, v/v) were collected, concentrated andrecrystallized from hexane-chloroform to give the titled compound (0.33g, 36%) as white crystals.

mp. 230.7-232.2° C.

¹H-NMR (CDCl₃) δ: 7.57 (1H, m), 7.71-7.77 (2H, m), 7.93 (1H, m), 8.39(1H, d, J=8.5 Hz), 8.53 (1H, d, J=7.9 Hz), 8.75 (1H, d, J=4.4 Hz).

IR(KBr): 1660, 1579, 1564, 1531, 1377, 1280, 736 cm⁻¹.

Elemental Analysis for C₁₃H₇N₂OSBr

Calcd. C, 48.92; H, 2.21; N, 8.78.

Found C, 48.92; H, 2.22; N, 8.53.

Example 242

6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-s-pyridinecarbonitrile

2,6-Pyridinecarbonitrile (1.00 g, 7.7 mmol) and methyl thiosalicylate(1.54 g, 9.1 mmol) were dissolved in toluene (6 ml), and triethylamine(3.0 ml, 21.5 mmol) was added thereto. The mixture was refluxed for 1hr. After cooling, the precipitates were collected by filtration andrecrystallized from hexane-chlorobenzene to give the titled compound(1.07 g, 52%) as pale yellow crystals.

mp. 263.7-264.2° C.

¹H-NMR (CDCl₃) δ: 7.74 (1H, m), 7.82 (1H, m), 7.97 (1H, d, J=7.9 Hz),8.32-8.37 (3H, m), 8.60 (1H, m).

IR(KBr): 3078, 2241, 1666, 1572, 1537, 1439, 1302, 1097, 995, 815, 742cm⁻¹.

Elemental Analysis for C₁₄H₇N₃OS

Calcd. C, 63.38; H, 2.66; N, 15.84.

Found C, 63.51; H, 2.96; N, 15.69.

Reference Example 86

Diethyl 2-pyridylmethylphoapshonate

A solution of lithium diisopropylamide (69 mmol) in tetrahydrofuran (145ml) was produced. To the solution, a solution of 2-picoline (5.0 g, 53mmol) in tetrahydrofuran (20 ml) was added dropwise at −78° C. Themixture was stirred at the same temperature for 10 minutes.Successively, a solution of diethyl chlorophosphate (13.8 g, 80 mmol) intetrahydrofuran (20 ml) was added dropwise to the mixture at −78° C.,and the mixture was stirred at the same temperature for 30 minutes. Thereaction mixture was combined with aqueous ammonium chloride solutionand extracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated, and the residue was subjected to a silica gel columnchromatography. The fractions eluted with ethyl acetate-methanol (8:1,v/v) were collected and concentrated to give the titled compound (3.6 g,29%).

¹H-NMR (CDCl₃) δ: 1.26 (6H, t, J=7.0 Hz), 3.38 (1H, s), 3.45 (1H, s),4.09 (4H, q, J=7.0 Hz), 7.16 (1H, m), 7.39 (1H, m) 7.64 (1H, m), 8.54(1H, d, J=4.6 Hz).

Reference Example 87

Diethyl 2-pyridylmethylphosphonate N-oxide

Diethyl 2-pyridylmethylphosphonate (3.1 g, 13 mmol) and3-chloroperbenzoic acid (77%, 4.0 g, 18 mmol) were dissolved in ethylacetate (50 ml), and the mixture was stirred at room temperature for 4hrs. The solvent was evaporated, and the residue was subjected to asilica gel column chromatography. The fractions eluted withmethanol-ethyl acetate (1:3, v/v) were collected and concentrated togive the titled compound (2.9 g, 88%).

¹H-NMR (CDCl₃) δ: 1.30 (6H, t, J=7.0 Hz), 3.66 (1H, s), 3.73 (1H, s),4.16 (4H, q, J=7.0 Hz), 7.16-7.27 (2H, m), 7.54 (1H, m), 8.27 (1H, d,J=5.7 Hz)

Reference Example 88

Diethyl (6-cyano-2-pyridyl)methylphosphonate

Diethyl 2-pyridylmethylphosphonate N-oxide (2.9 g, 12 mmol) wasdissolved in nitroethane (30 ml), and trimethylsilyl cyanide (2.6 g, 26mmol) and N,N-dimethylcarbamoyl chloride (2.7 g, 25 mmol) were addedthereto. The mixture was stirred at room temperature for 30 hrs. Thesolvent was evaporated, and the residue was subjected to a silica gelcolumn chromatography. The fractions eluted with ethyl acetate-methanol(20:1, v/v) were collected and concentrated to give the titled compound(1.5 g, 49%).

¹H-NMR (CDCl₃) δ: 1.29 (6H, t, J=7.0 Hz), 3.41 (1H, s), 3.49 (1H, s),4.11 (4H, m), 7.58-7.64 (2H, m), 7.79 (1H, m).

IR(KBr): 2984, 2237, 1587, 1450, 1249, 1053, 1026, 968 cm⁻¹.

Example 243

Diethyl [6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methylphospho nate

Diethyl (6-cyano-2-pyridyl)methylphosphonate (1.4 g, 5.8 mmol) andmethyl thiosalicylate (1.9 g, 11.6 mmol) were dissolved in toluene (8ml), and triethylamine (4.0 ml, 28.6 mmol) was added thereto. Themixture was refluxed for 13 hrs. The solvent was evaporated, and theresidue was subjected to a silica gel column chromatography. Thefractions eluted with ethyl acetate-methanol (10:1, v/v) were collected,concentrated and recrystallized from diisopropyl ether-ethanol to givethe titled compound (510 mg, 22%) as pale yellow crystals.

mp. 115.5-116.5° C.

¹H-NMR (CDCl₃) δ: 1.29 (6H, t, J=7.0 Hz), 3.50 (1H, s), 3.58 (1H, s),4.12 (4H, m), 7.60-7.72 (4H, m), 7.86 (1H, m), 8.43 (1H, d, J=7.8 Hz),8.55 (1H, m).

IR(KBr): 2982, 1662, 1572, 1537, 1302, 1275, 1250, 1051, 1028, 966 cm⁻¹.

Elemental Analysis for C₁₈H₁₉N₂O₄SP

Calcd. C, 55.38; H, 4.91; N, 7.18.

Found C, 55.34; H, 4.89; N, 7.21.

Example 244

[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methylphospho ric acid

Diethyl [6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methylphospho nate(0.20 g, 0.51 mmol) and iodetrimethylsilane (0.31 g, 1.58 mmol) weredissolved in dichloromethane (10 ml), and the mixture was stirred atroom temperature for 1 hr. The reaction mixture was combined withmethanol, and the solvent was evaporated. The residue was recrystallizedfrom diisopropyl ether-methanol to give the titled compound (0.05 g,30%) as pale yellow crystals.

mp. 254.0° C. (decomposed)

¹H-NMR (DMSO-d₆) δ: 3.31 (1H, s), 3.38 (1H, s), 7.69-7.75 (2H, m), 7.84(1H, m), 7.95 (1H, d, J=7.9 Hz), 8.03 (1H, m), 8.21 (1H, d, J=8.0 Hz),8.36 (1H, dd, J=1.1, 7.9 Hz), 10.90 (2H, br s).

IR(KBr): 2905, 1589, 1570, 1529, 1440, 1317, 1012, 929 cm⁻¹.

Elemental Analysis for C₁₄H₁₁N₂O₄PS 0.25H₂O

Calcd. C, 49.63; H, 3.42; N, 8.27.

Found C, 49.80; H, 3.36; N, 8.26.

Reference Example 89

Diethyl (E)-2-(2-pyridyl)ethenylphosphonate

A solution of tetraethyl methylenediphosphonate (3.7 g, 13 mmol) intetrahydrofuran (5 ml) was added dropwise to a mixture of sodium hydride(60% in oil, 750 mg, 18 mmol) and tetrahydrofuran (15 ml) at 0° C., andthe mixture was stirred at the same temperature for 20 minutes.Successively, a solution of 2-pyridinecarbaldehyde (1.3 g, 12 mmol) intetrahydrofuran (5 ml) was added dropwise to the mixture at 0° C., andthe mixture was stirred at room temperature for 30 minutes. The reactionmixture was combined with water and extracted with ethyl acetate. Theorganic layer was washed with brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated, and the residue was subjected to asilica gel column chromatography. The fractions eluted with ethylacetate-methanol (20:1, v/v) were collected and concentrated to give thetitled compound (2.7 g, 94%).

¹H-NMR (CDCl₃) δ: 1.33 (6H, t, J=7.0 Hz), 4.13 (4H, q, J=7.0 Hz), 6.88(1H, dd, J=17.1, 19.3 Hz), 7.27 (1H, m), 7.38 (1H, d, J=7.7 Hz), 7.52(1H, dd, J=17.1, 21.7 Hz), 7.72 (1H, m), 8.64 (1H, d, J=4.0 Hz).

Reference Example 90

Diethyl 2-(2-pyridyl)ethylphosphanate

Diethyl (E)-2-(2-pyridyl)ethenylphosphonate (2.7 g, 11.2 mmol) wasdissolved in ethanol (80 ml), and 10% palladium-carbon (300 mg) wasadded thereto. The mixture was stirred under hydrogen atmosphere at roomtemperature for 3 hrs. Palladium-carbon was filtered off, and thefiltrate was concentrated to give the titled compound (2.7 g, 100%).

¹H-NMR (CDCl₃) δ: 1.30 (6H, t, J=7.0 Hz), 2.24 (2H, m), 3.08 (2H, m),4.09 (4H, m), 7.13 (1H, m), 7.19 (1H, d, J=7.7 Hz), 7.60 (1H, m), 8.53(1H, d, J=4.5 Hz).

Reference Example 91

Diethyl 2-(2-pyridyl)ethylphosphonate N-oxide

Diethyl 2-(2-pyridyl)ethylphosphonate (2.7 g, 11 mmol) and3-chloroperbenzoic acid (77%, 3.2 g, 14 mmol) were dissolved in ethylacetate (50 ml), and the mixture was stirred at room temperature for 4hrs. The solvent was evaporated, and the residue was subjected to asilica gel column chromatography. The fractions eluted withmethanol-ethyl acetate (1:3, v/v) were collected and concentrated togive the titled compound (2.8 g, 99%).

¹H-NMR (CDCl₃) δ: 1.29 (6H, t, J=7.0 Hz), 2.23-2.34 (2H, m), 3.13-3.23(2H, m), 4.08 (4H, m), 7.16-7.25 (2H, m), 7.32 (1H, m), 8.24 (1H, m).

Reference Example 92

Diethyl 2-(6-cyano-2-pyridyl)ethylphosphonate

Diethyl 2-(2-pyridyl)ethylphosphonate N-oxide (2.8 g, 11 mmol) wasdissolved in nitroethane (30 ml), and trimethylsilyl cyanide (2.2 g, 22mmol) and N,N-dimethylcarbamoyl chloride (2.4 g, 22 mmol) were addedthereto. The mixture was stirred at room temperature for 28 hrs. Thesolvent was evaporated, and the residue was subjected to a silica gelcolumn chromatography. The fractions eluted with ethyl acetate-methanol(15:1) were collected and concentrated to give the titled compound (1.7g, 59%).

¹H-NMR (CDCl₃) δ: 1.31 (6H, t, J=7.0 Hz), 2.26 (2H, m), 3.14 (2H, m),4.10 (4H, m), 7.43 (1H, d, J=7.8 Hz), 7.56 (1H, d, J=7.2 Hz), 7.75 (1H,dd, J=7.2, 7.8 Hz).

IR(KBr): 3447, 2984, 2237, 1589, 1452, 1232, 1055, 1030, 970, 808 cm⁻¹.

Example 245

Diethyl 2-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]ethylphosphonate

Diethyl 2-(6-cyano-2-pyridyl)ethylphosphonate (0.80 g, 2.9 mmol) andmethyl thiosalicylate (1.00 g, 5.9 mmol) were dissolved in toluene (4ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. Themixture was refluxed for 5 hrs. After cooling, the precipitated crystalswere collected by filtration and recrystallized from diisopropylether-ethanol to give the titled compound (0.61 g, 50%) as whitecrystals.

mp. 148.8-149.8° C.

¹H-NMR (CDCl₃) δ: 1.33 (6H, t, J=7.0 Hz), 2.43 (2H, m), 3.21 (2H, m),4.15 (4H, m), 7.43 (1H, d, J=7.5 Hz), 7.61-7.71 (3H, m), 7.82 (1H, m),8.38 (1H, d, J=7.5 Hz), 8.55 (1H, m).

IR(KBr): 2978, 1655, 1574, 1537, 1305, 1286, 1242, 1049, 1026, 966 cm⁻¹.

Elemental Analysis for C₁₉H₂₁N₂O₄SP

Calcd. C, 56.43; H, 5.23; N, 6.93.

Found C, 56.40; H, 5.01; N, 6.88.

Example 246

2-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]ethylphosph oric acid

Diethyl 2-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]ethylphosphonate (0.42 g, 1.0 mmol) and iodetrimethylsilane (0.65 g, 3.2 mmol) weredissolved in dichloromethane (10 ml), and the mixture was stirred at 0°C. for 1 hr. The reaction mixture was combined with methanol, and thesolvent was evaporated. The residue was recrystallized from diisopropylether-methanol to give the titled compound (0.21 g, 60%) as pale yellowcrystals.

mp. 235.3-237.2° C.

¹H-NMR (DMSO-d₆) δ: 2.02-2.14 (2H, m), 3.04-3.13 (2H, m) 7.67-7.74 (2H,m), 7.82 (1H, m), 7.95-8.03 (2H, m), 8.19 (1H, d, J=7.7 Hz), 8.35 (1H,d, J=7.8 Hz).

IR(KBr): 2808, 2305, 1631, 1570, 1525, 1163, 1014, 933 cm⁻¹.

Elemental Analysis for C₁₅H₁₃N₂O₄PS ·1.0H₂O

Calcd. C, 49.18; H, 4.13; N, 7.65.

Found C, 49.42; H, 4.33; N, 7.48.

Reference Example 93

Diethyl (E)-2-(4-pyridyl)ethenylphosphate

A solution of tetraethyl methylenediphosphonate (13.3 g, 46 mmol) intetrahydrofuran (30 ml) was added dropwise to a solution of sodiumhydride (60% in oil, 2.6 g, 65 mmol) and tetrahydrofuran (10 ml) at 0°C., and the mixture was stirred at the same temperature for 30 minutes.Successively, a solution of 4-pyridinecarbaldehyde (4.6 g, 43 mmol) intetrahydrofuran (30 ml) was added dropwise to the mixture at 0° C., andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was combined with water and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over magnesiumsulfate. The solvent was evaporated to give the titled compound (10.3 g,100%).

¹H-NMR (CDCl₃) δ: 1.37 (6H, m), 4.17 (4H, m), 6.51 (1H, dd, J=17.4, 17.4Hz), 7.40 (2H, m), 7.44 (1H, dd, J=17.4, 22.0 Hz), 8.66 (2H, m)

Reference Example 94

Diethyl 2-(4-pyridyl)ethylphosphonate

Diethyl (E)-2-(4-pyridyl)ethenylphosphonate (10.3 g, 42 mmol) wasdissolved in ethanol (25 ml), and 10% palladium-carbon (1.0 g) was addedthereto. The mixture was stirred under hydrogen atmosphere at roomtemperature for 5 hrs. Palladium-carbon was filtered off, and thefiltrate was concentrated to give the titled compound (10.3 g, 100%).

¹H-NMR (CDCl₃) δ: 1.32 (6H, m), 2.05 (2H, m), 2.93 (2H, m), 4.09 (4H,m), 7.19 (2H, d, J=5.8 Hz), 8.53 (2H, d, J=5.8 Hz).

Reference Example 95

Diethyl 2-(4-pyridyl)ethylphosphonate N-oxide

Diethyl 2-(4-pyridyl)ethylphosphonate (10.3 g, 42 mmol) and3-chloroperbenzoic acid (77%, 12.3 g, 54 mmol) were dissolved in ethylacetate (200 ml), and the mixture was stirred at room temperature for 5hrs. The solvent was evaporated, and the residue was subjected to asilica gel column chromatography. The fractions eluted withethanol-ethyl acetate (1:1, v/v) were collected and concentrated to givethe titled compound (9.9 g, 99%).

¹H-NMR (CDCl₃) δ: 1.32 (6H, t, J=7.0 Hz), 2.03 (2H, m), 2.94 (2H, m),4.09 (4H, q, J=7.0 Hz), 7.16 (2H, d, J=5.7 Hz), 8.17 (2H, d, J=5.7 Hz).

Reference Example 96

Diethyl 2-(2-cyano-4-pyridyl)ethylphosphonate

Diethyl 2-(4-pyridyl)ethylphosphonate N-oxide (9.9 g, 38 mmol) wasdissolved in nitroethane (200 ml), and trimethylsilyl cyanide (7.5 g, 75mmol) and N,N-dimethylcarbamoyl chloride (6.1 g, 56 mmol) were addedthereto. The mixture was stirred at room temperature for 12 hrs. Thesolvent was evaporated, and the residue was subjected to a silica gelcolumn chromatography. The fractions eluted with ethyl acetate-methanol(15:1) were collected and concentrated to give the titled compound (7.3g, 71%).

¹H-NMR (CDCl₃) δ: 1.31 (6H, t, J=7.0 Hz), 2.06 (2H, m), 2.98 (2H, m),4.10 (4H, m), 7.38 (1H, dd, J=0.7, 5.0 Hz), 7.57 (1H, d, J=0.7 Hz), 8.62(1H, d, J=5.0 Hz).

Example 247

Diethyl 2-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]ethylphosphonate

Diethyl 2-(2-cyano-4-pyridyl)ethylphosphonate (1.4 g, 5.4 mmol) andmethyl thiosalicylate (1.8 g, 10.9 mmol) were dissolved in toluene (8ml), and triethylamine (4.0 ml, 28.6 mmol) was added thereto. Themixture was refluxed for 6 hrs. The solvent was evaporated, and theresidue was subjected to a silica gel column chromatography. Thefractions eluted with ethyl acetate-methanol (10:1, v/v) were collected,concentrated and recrystallized from hexane-ethyl acetate to give thetitled compound (0.96 g, 43%) as white crystals.

mp. 102.0-103.2° C.

¹H-NMR (CDCl₃) δ: 1.33 (6H, t, J=7.0 Hz), 2.11 (2H, m), 3.03 (2H, m),4.13 (4H, m), 7.42 (1H, dd, J=1.6, 4.9 Hz), 7.61-7.70 (3H, m), 8.43 (1H,d, J=1.0 Hz), 8.56 (1H, m), 8.65 (1H, d, J=4.9 Hz).

IR(KBr): 2982, 2934, 1662, 1570, 1533, 1280, 1236, 1053, 1030, 966, 812cm⁻¹.

Elemental Analysis for C₁₉H₂₁N₂O₄SP

Calcd. C, 56.43; H, 5.23; N, 6.93.

Found C, 56.23; H, 5.30; N, 6.58.

Example 248

Diethyl 2-[2-(7-chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]ethylphosphonate

Diethyl 2-(2-cyano-4-pyridyl)ethylphosphonate (1.7 g, 6.4 mmol) and4-chlorothiosalicylic acid (2.4 g, 12.8 mmol) were dissolved in pyridine(30 ml), and the mixture was refluxed for 13 hrs. The solvent wasevaporated, and the residue was subjected to a silica gel columnchromatography. The fractions eluted with ethyl acetate-chloroform (1:1,v/v) were collected, concentrated and recrystallized fromhexane-tetrahydrofuran to give the titled compound (0.43 g, 15%) aswhite crystals.

mp. 137.7-139.1° C.

¹H-NMR (CDCl₃) δ: 1.33 (6H, t, J=7.1 Hz), 2.11 (2H, m), 3.04 (2H, m),4.14 (4H, m), 7.42 (1H, d, J=4.8 Hz), 7.56-7.60 (2H, m), 8.40 (1H, s),8.49 (1H, d, J=8.2 Hz), 8.64 (1H, d, J=4.8 Hz).

IR(KBr): 2982, 1666, 1585, 1566, 1537, 1278, 1240, 1093, 1055, 1028, 964cm⁻¹.

Elemental Analysis for C₁₉H₂₀N₂O₄SPCl·0.25H₂O

Calcd. C, 51.47; H, 4.66; N, 6.32.

Found C, 51.67; H, 4.40; N, 5.97.

Example 249

2-[6-[(Ethylthio)methyl]-2-pyridyl]-4H-1,3-benzothiazine-4-one

Ethyl mercaptan (0.25 g, 3.30 mmol) and sodium hydride (60% in oil, 0.15g, 3.60 mmol) were dissolved in DMF (30 ml), and6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl methanesulfonate (1.05 g,3.00 mmol) was added thereto. The reaction mixture was stirred at roomtemperature for 18 hrs and combined with ethyl acetate and water. Theorganic layer was washed with saturated brine and dried over magnesiumsulfate. The solvent was evaporated, and the residue was recrystallizedfrom n-hexane-ethyl acetate to give the titled compound (0.23 g, 24%) aspale yellow crystals.

mp. 142.0-143.5° C.

¹H-NMR (CDCl₃) δ: 1.32 (3H, t, J=7.3 Hz), 2.59 (2H, q, J=7.3 Hz), 3.95(2H, s), 7.61-7.73 (4H, m), 7.87 (1H, t, J=7.8 Hz), 8.41 (1H, d, J=7.7Hz), 8.54-8.56 (1H, m).

IR(KBr): 1658, 1589, 1570, 1531, 1439, 1300, 1095, 993, 742 cm⁻¹.

Elemental Analysis for C₁₆H₁₄N₂OS₂

Calcd. C, 61.12; H, 4.49; N, 8.91.

Found C, 60.87; H, 4.41; N, 8.67.

Example 250

2-[6-[(Ethylsulfinyl)methyl]-2-pyridyl]-4H-1,3-benzothiazin e-4-one

2-[6-[(Ethylthio)methyl]-2-pyridyl]-4H-1,3-benzothiaz ine-4-one (0.10 g,0.32 mmol) was dissolved in chloroform (50 ml), and a solution of3-chloroperbenzoic acid (ca. 77%, 0.071 g, 0.32 mmol) in chloroform (10ml) was added dropwise thereto. The mixture was stirred at roomtemperature for 1 hr. The solvent was evaporated, and the residue wasrecrystallized from n-hexane-ethyl acetate to give the titled compound(0.095 g, 91%) as pale yellow crystals.

mp. 188.5-190.0° C.

¹H-NMR (CDCl₃) δ: 1.29 (3H, s), 3.11, 3.30 (2H, q_(AB), J=13.8 Hz),4.21, 4.32 (2H, q_(AB), J=12.8 Hz), 7.59-7.70 (4H, m), 7.94 (1H, t,J=7.8 Hz), 8.51-8.57 (2H, m).

IR(KBr): 1652, 1568, 1531, 1454, 1437, 1298, 1095, 1028, 995, 744 cm⁻¹.

Elemental Analysis for C₁₆H₁₄N₂O₂S₂

Calcd. C, 58.16; H, 4.27; N, 8.48.

Found C, 57.93; H, 4.18; N, 8.20.

Example 251

2-[6-[(Ethylsulfonyl)methyl]-2-pyridyl]-4H-1,3-benzothiazin e-4-one

2-[6-[(Ethylthio)methyl]-2-pyridyl]-4H-1,3-benzothiaz ine-4-one (0.10 g,0.32 mmol) was dissolved in chloroform (50 ml), and a solution of3-chloroperbenzoic acid (ca. 77%, 0.14 g, 0.64 mmol) in chloroform (10ml) was added dropwise thereto. The mixture was stirred at roomtemperature for 3 hrs. The solvent was evaporated, and the residue wasrecrystallized from n-hexane-ethyl acetate to give the titled compound(0.043 g, 39%) as white crystals.

mp. 188.5-190.0° C.

¹H-NMR (CDCl₃) δ: 1.43 (3H, s), 3.57 (2H, q, J=7.3 Hz), 4.55 (2H, s),7.59-7.70 (4H, m), 7.94 (1H, t, J=7.8 Hz), 8.51-8.57 (2H, m).

IR(KBr): 1652, 1568, 1531, 1454, 1437, 1298, 1114, 1095, 995, 744 cm⁻¹.

Elemental Analysis for C₁₆H₁₄N₂O₃S₂

Calcd. C, 55.47; H, 4.07; N, 8.09.

Found C, 55.53; H, 4.18; N, 8.21.

Example 252

2-[6-[(n-Propylthio)methyl]-2-pyridyl]-4H-1,3-benzothiazine -4-one

n-Propyl mercaptan (0.25 g, 3.30 mmol) and sodium hydride (60% in oil,0.15 g, 3.60 mmol) were dissolved in DMF (30 ml), and6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl methanesulfonate (1.05 g,3.00 mmol) was added thereto. The reaction mixture was stirred at roomtemperature for 18 hrs, combined with ethyl acetate and water. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated, and the residue wasrecrystallized from n-hexane-ethyl acetate to give the titled compound(0.20 g, 20%) as pale yellow crystals.

mp. 115.5-113.0° C.

¹H-NMR (CDCl₃) δ: 0.99 (2H, t, J=7.3 Hz), 1.62-1.74 (2H, m), 2.55 (2H,t, J=7.3 Hz), 3.92 (2H, s), 7.60-7.71 (4H, m), 7.87 (1H, t, J=7.8 Hz),8.41 (1H, d, J=7.7 Hz), 8.54-8.57 (1H, m).

IR(KBr): 1666, 1572, 1537, 1439, 1300, 1095, 993, 746 cm⁻¹.

Elemental Analysis for C₁₆H₁₄N₂OS₂

Calcd. C, 62.16; H, 4.91; N, 8.53.

Found C, 62.20; H, 4.69; N, 8.44.

Example 253

2-[6-(n-Propylsulfinyl)methyl]-2-pyridyl]-4H-1,3-benzothiaz ine-4-one

0.2-[6-[(n-Propylthio)methyl]-2-pyridyl]-4H-1,3-benzoth iazine-4-one(0.080 g, 0.24 mmol) was dissolved in chloroform (50 ml), and a solutionof 3-chloroperbenzoic acid (ca. 77%, 0.055 g, 0.24 mmol) in chloroform(10 ml) was added dropwise thereto. The mixture was stirred at roomtemperature for 1 hr. The solvent was evaporated, and the residue wasrecrystallized from n-hexane-ethyl acetate to give the titled compound(0.071 g, 85%) as pale yellow crystals.

mp. 171.0-173.0° C.

¹H-NMR (CDCl₃) δ: 1.05 (3H, t, J=7.3 Hz), 1.68-1.70 (2H, m), 3.10, 3.19(2H, q_(AB), J=13.8 Hz), 4.16-4.25 (2H, q_(AB), J=12.8 Hz), 7.60-7.71(4H, m), 7.87 (1H, t, J=7.8 Hz), 8.41 (1H, d, J=7.7 Hz), 8.54-8.57 (1H,m).

IR(KBr): 1664, 1572, 1537, 1438, 1300, 1095, 993, 746 cm⁻¹.

Elemental Analysis for C₁₇H₁₆N₂O₂S₂

Calcd. C, 59.28; H, 4.68; N, 8.13.

Found C, 59.15; H, 4.72; N, 8.41.

Example 254

2-[6-[(n-Propylsulfonyl)methyl)-2-pyridyl]-4H-1,3-benzothia zine-4-one

2-[6-[(n-Propylthio)methyl]-2-pyridyl]-4H-1,3-benzoth iazine-4-one (0.10g, 0.30 mmol) was dissolved in chloroform (50 ml), and a solution of3-chloroperbenzoic acid (ca. 77%, 0.14 g, 0.61 mmol) in chloroform (10ml) was added dropwise thereto. The mixture was stirred at roomtemperature for 3 hrs. The solvent was evaporated, and the residue wasrecrystallized from n-hexane-ethyl acetate to give the titled compound(0.080 g, 73%) as white crystals.

mp. 177.0-179.0° C.

¹H-NMR (CDCl₃) δ: 1.07 (3H, t, J=7.3 Hz), 1.80-1.81 (2H, m), 3.55 (2H,m), 4.52 (2H, s), 7.60-7.71 (4H, m), 7.87 (1H, t, J=7.8 Hz), 8.41 (1H,d, J=7.7 Hz), 8.54-8.58 (1H, m).

IR(KBr): 1664, 1572, 1537, 1438, 1300, 1114, 1095, 993, 746 cm⁻¹.

Elemental Analysis for C₁₇H₁₆N₂O₃S₂

Calcd. C, 56.65; H, 4.47; N, 7.77.

Found C, 56.45; H, 4.72; N, 7.80.

Example 255

2-[6-[(Benzylthio)methyl]-2-pyridyl]-4H-1,3-benzothiazine-4-one

Benzyl mercaptan (0.41 g, 3.30 mmol) and sodium hydride (60% in oil,0.15 g, 3.60 mmol) were dissolved in DMF (30 ml), and6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl methanesulfonate (1.05 g,3.00 mmol) was added thereto. The reaction mixture was stirred at roomtemperature for 18 hrs and combined with ethyl acetate and water. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated, and the residue wasrecrystallized from n-hexane-ethyl acetate to give the titled compound(0.18 g, 16%) as pale yellow crystals.

mp. 126.0-128.0° C.

¹H-NMR (CDCl₃) δ: 3.80 (2H, s), 3.83 (2H, s), 7.25-7.41 (5H, m)7.61-7.69 (4H, m), 7.84 (1H, t, J=7.8 Hz), 8.41 (1H, d, J=7.7 Hz),8.55-8.58 (1H, m).

IR(KBr): 1658, 1572, 1537, 1439, 1300, 1095, 993, 742 cm⁻¹.

Elemental Analysis for C₂₁H₁₆N₂OS₂

Calcd. C, 66.99; H, 4.28; N, 7.44.

Found C, 66.89; H, 4.20; N, 7.55.

Example 256

2-[6-[(Benzylsulfinyl)methyl]-2-pyridyl]-4H-1,3-benzothiazi ne-4-one

2-[6-[(Benzylthio)methyl]-2-pyridyl]-4H-1,3-benzothia zine-4-one (0.080g, 0.22 mmol) was dissolved in chloroform (50 ml), and a solution of3-chloroperbenzoic acid (ca. 77%, 0.037 g, 0.22 mmol) in chloroform (10ml) was added dropwise thereto. The mixture was stirred at roomtemperature for 1 hr. The solvent was evaporated, and the residue wasrecrystallized from n-hexane-ethyl acetate to give the titled compound(0.053 g, 64%) as pale yellow crystals.

mp. 187.0-189.0° C.

¹H-NMR (CDCl₃) δ: 4.15, 4.24 (2H, q_(AB), J=13.8 Hz), 4.23, 4.32 (2H,q_(AB), J=12.6 Hz), 7.25-7.41 (5H, m), 7.61-7.69 (4H, m), 7.84 (1H, t,J=7.8 Hz), 8.41 (1H, d, J=7.7 Hz), 8.55-8.58 (1H, m).

IR(KBr): 1660, 1572, 1537, 1439, 1300, 1095, 993, 742 cm⁻¹.

Elemental Analysis for C₂₁H₁₆N₂O₂S₂

Calcd. C, 64.26; H, 4.11; N, 7.14.

Found C, 64.49; H, 4.20; N, 7.35.

Example 257

2-[6-[(Benzylsulfonyl)methyl]-2-pyridyl]-4H-1,3-benzothiazi ne-4-one

2-[6-[(Benzylthio)methyl]-2-pyridyl]-4H-1,3-benzothia zine-4-one (0.13g, 0.35 mmol) was dissolved in chloroform (50 ml), and a solution of3-chloroperbenzoic acid (ca. 77%, 0.16 g, 0.71 mmol) in chloroform (10ml) was added dropwise thereto. The mixture was stirred at roomtemperature for 3 hrs. The solvent was evaporated, and the residue wasrecrystallized from n-hexane-ethyl acetate to give the titled compound(0.084 g, 54%) as white crystals.

mp. 246.0-248.0° C.

¹H-NMR (CDCl₃) δ: 4.46 (2H, s), 4.53 (2H, s), 7.25-7.43 (5H, m),7.61-7.69 (4H, m), 7.84 (1H, t, J=7.8 Hz), 8.41 (1H, d, J=7.7 Hz),8.55-8.58 (1H, m).

IR(KBr): 1658, 1572, 1537, 1439, 1300, 1115, 1095, 993, 742 cm⁻¹.

Elemental Analysis for C₂₁H₁₆N₂O₃S₂

Calcd. C, 61.74; H, 3.95; N, 6.86.

Found C, 62.01; H, 4.21; N, 6.58.

Example 258

Methyl ({[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methyl}thio)acetate

Methyl thioglycolate (0.35 g, 3.30 mmol) and sodium hydride (60% in oil,0.15 g, 3.60 mmol) were dissolved in DMF (30 ml), and6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl methanesulfonate (1.05 g,3.00 mmol) was added thereto. The reaction mixture was stirred at roomtemperature for 18 hrs and combined with ethyl acetate and water. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue wasrecrystallized from ethanol to give the titled compound (0.55 g, 51%) aspale yellow crystals.

mp. 108.0-110.0° C.

¹H-NMR (CDCl₃) δ: 3.35 (2H, s), 3.73 (3H, s), 4.06 (2H, s), 7.59-7.71(4H, m), 7.88 (1H, t, J=7.8 Hz), 8.42 (1H, d, J=7.7 Hz), 8.55 (1H, d,J=8.5 Hz)

IR(KBr): 1730, 1658, 1651, 1572, 1537, 1435, 1300, 1097, 993, 744 cm⁻¹.

Elemental Analysis for C₁₇H₁₄N₂O₃S₂

Calcd. C, 56.96; H, 3.94; N, 7.82.

Found C, 56.84; H, 3.99; N, 7.70.

Example 259

Methyl ({[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methyl}sulfinyl)acetate

Methyl ({[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methyl}thio)acetate (0.10 g, 0.28 mmol) was dissolved in chloroform (50 ml), and asolution of 3-chloroperbenzoic acid (ca. 77%, 0.064 g, 0.28 mmol) inchloroform (10 ml) was added dropwise thereto. The mixture was stirredat room temperature for 1 hr. The solvent was evaporated, and theresidue was recrystallized from ethanol to give the titled compound(0.096 g, 92%) as pale yellow crystals.

mp. 149.5-151.0° C.

¹H-NMR (CDCl₃) δ: 3.70, 4.00 (2H, q_(AB), J=14.3 Hz), 3.83 (3H, s),4.38, 4.55 (2H, q_(AB), J=13.1 Hz), 7.60-7.73 (4H, m), 7.95 (1H, t,J=7.8 Hz), 8.52-8.58 (2H, m).

IR(KBr): 1732, 1651, 1570, 1531, 1435, 1277, 1234, 1097, 912, 742 cm⁻¹.

Elemental Analysis for C₁₇H₁₄N₂O₄S₂

Calcd. C, 54.53; H, 3.77; N, 7.48.

Found C, 54.43; H, 3.73; N, 7.26.

Example 260

Methyl ({[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methyl}sulfonyl)acetate

Methyl ({[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methyl}thio)acetate (0.20 g, 0.56 mmol) was dissolved in chloroform (50 ml), and asolution of 3-chloroperbenzoic acid (ca. 77%, 0.25 g, 1.12 mmol) inchloroform (10 ml) was added dropwise thereto. The mixture was stirredat room temperature for 3 hrs. The solvent was evaporated, and theresidue was recrystallized from ethanol to give the titled compound(0.043 g, 20%) as white crystals.

mp. 205.0-207.0° C.

¹H-NMR (CDCl₃) δ: 3.73 (3H, s), 4.35 (2H, s), 4.66 (2H, s), 7.59-7.71(4H, m), 7.88 (1H, t, J=7.8 Hz), 8.42 (1H, d, J=7.7 Hz), 8.55 (1H, d,J=8.5 Hz).

IR(KBr): 1732, 1655, 1570, 1533, 1439, 1302, 1114, 1097, 995, 738 cm⁻¹.

Elemental Analysis for C₁₇H₁₄N₂O₅S₂

Calcd. C, 52.30; H, 3.64; N, 8.43.

Found C, 52.15; H, 3.62; N, 8.38.

Example 261

2-[6-(Methylsulfinyl)-3-pyridyl]-4H-1,3-benzothiazine-4-one

2-[6-(Methylthio)-3-pyridyl]-4H-1,3-benzothiazine-4-o ne (0.28 g, 1.00mmol) was dissolved in chloroform (30 ml), and a solution of3-chloroperbenzoic acid (ca. 77%, 0.23 g, 1.00 mmol) in chloroform (10ml) was added dropwise thereto. The mixture was stirred at roomtemperature for 1 hr. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the titled compound (0.085 g, 28%)as pale yellow crystals.

mp. 195.0-196.5° C.

¹H-NMR (CDCl₃) δ: ¹H-NMR (CDCl₃) δ: 2.93 (3H, s), 7.59-7.61 (1H, m),7.69-7.75 (2H, m), 8.21-8.24 (1H, m), 8.56-8.59 (1H, m), 8.69-8.72 (1H,m), 9.37-9.38 (1H, m).

IR(KBr): 1660, 1572, 1520, 1439, 1361, 1299, 1095, 1053, 923, 742 cm⁻¹.

Elemental Analysis for C₁₄H₁₀N₂O₂S₂

Calcd. C, 55.61; H, 3.33; N, 9.26.

Found C, 55.49; H, 3.27; N, 9.39.

Example 262

2-[6-(Methylsulfonyl)-3-pyridyl]-4H-1,3-benzothiazine-4-one

2-[6-(Methylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-o ne (0.56 g, 2.00mmol) was dissolved in chloroform (30 ml), and a solution of3-chloroperbenzoic acid (ca. 77%, 0.90 g, 4.00 mmol) in chloroform (10ml) was added dropwise thereto. The mixture was stirred at roomtemperature for 3 hrs. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the titled compound (0.090 g, 14%)as pale yellow crystals.

mp. 205.0-207.0° C.

¹H-NMR (CDCl₃) δ: 3.31 (3H, s), 7.60-7.63 (1H, m), 7.71-7.77 (2H, m),8.25-8.28 (1H, m), 8.57-8.60 (1H, m), 8.72-8.76 (1H, m), 9.44-9.45 (1H,m).

IR(KBr): 1658, 1572, 1520, 1439, 1292, 1238, 1163, 1095, 912, 742 cm⁻¹.

Elemental Analysis for C₁₄H₁₀N₂O₃S₂

Calcd. C, 52.82; H, 3.17; N, 8.80.

Found C, 52.89; H, 3.47; N, 8.99.

Example 263

2-[2-(Methylsulfinyl)-4-pyridyl]-4H-1,3-benzothiazine-4-one

2-[2-(Methylthio)-4-pyridyl]-4H-1,3-benzothiazine-4-o ne (0.28 g, 1.00mmol) was dissolved in chloroform (30 ml), and a solution of3-chloroperbenzoic acid (ca. 77%, 0.23 g, 1.00 mmol) in chloroform (10ml) was added dropwise thereto. The mixture was stirred at roomtemperature for 1 hr. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the titled compound (0.096 g, 32%)as pale yellow crystals.

mp. 172.5-174.0° C.

¹H-NMR (CDCl₃) δ: ¹H-NMR (CDCl₃) δ: 2.93 (3H, s), 7.60-7.62 (1H, m),7.70-7.76 (2H, m), 8.21-8.23 (1H, m), 8.56-8.59 (1H, m), 8.64-8.65 (1H,m), 8.84-8.86 (1H, m).

IR(KBr): 1666, 1587, 1572, 1518, 1439, 1290, 1242, 1093, 1049, 956, 744cm⁻¹.

Elemental Analysis for C₁₄H₁₀N₂O₂S₂

Calcd. C, 55.61; H, 3.33; N, 9.26.

Found C, 55.45; H, 3.35; N, 9.24.

Example 264

2-[2-(Methylsulfonyl)-4-pyridyl]-4H-1,3-benzothiazine-4-one

2-[2-(Methylthio)-4-pyridyl]-4H-1,3-benzothiazine-4-o ne (0.56 g, 2.00mmol) was dissolved in chloroform (30 ml), and a solution of3-chloroperbenzoic acid (ca. 77%, 0.90 g, 4.00 mmol) in chloroform (10ml) was added dropwise thereto. The mixture was stirred at roomtemperature for 3 hrs. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the titled compound (0.030 g, 5%) aspale yellow crystals.

mp. 189.5-191.5° C.

¹H-NMR (CDCl₃) δ: 3.31 (3H, s), 7.61-7.64 (1H, m), 7.70-7.78 (2H, m),8.34-8.36 (1H, m), 8.56-8.59 (1H, m), 8.72-8.73 (1H, m) 8.96 (1H, d,J=5.0 Hz).

IR(KBr): 1666, 1589, 1572, 1520, 1440, 1294, 1147, 1095, 956, 744 cm⁻¹.

Elemental Analysis for C₁₄H₁₀N₂O₃S₂ 0.25H₂O

Calcd. C, 52.08; H, 3.27; N, 8.67.

Found C, 52.38; H, 3.21; N, 8.42.

Example 265

2-(6-{[4-(4-Fluorophenyl)-1-piperazinyl]methyl}-2-pyridyl)-4H-1,3-benzothiazine-4-one

6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl methanesulfonate (0.30 g,0.86 mmol), triethylamine (0.20 ml, 1.42 mmol) and1-(4-fluorophenyl)piperazine (0.17 g, 0.95 mmol) were dissolved in DMF(30 ml), and the mixture was stirred at 70° C. for 18 hrs. The reactionmixture was combined with ethyl acetate and water. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated, and the residue was recrystallized fromn-hexane-ethyl acetate to give the titled compound (0.19 g, 50%) as paleyellow crystals.

mp. 156.0-157.0° C.

¹H-NMR (CDCl₃) δ: 2.78 (2H, t, J=4.7 Hz), 3.18 (2H, t, J=4.7 Hz), 3.88(2H, s), 6.88-6.99 (4H, m), 7.61-7.75 (4H, m), 7.89 (1H, t, J=7.7 Hz),8.55 (1H, d, J=7.7 Hz), 8.54-8.55 (1H, m).

IR(KBr): 1658, 1589, 1572, 1531, 1439, 1300, 1277, 1234, 1095, 993, 744cm⁻¹.

Elemental Analysis for C₂₄H₂₁FN₄OS

Calcd. C, 66.65; H, 4.89; N, 12.99.

Found C, 66.55; H, 4.80; N, 13.01.

Example 266

2-(6-(1-Piperidinomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one

6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl methanesulfonate (0.30 g,0.86 mmol), triethylamine (0.20 ml, 1.42 mmol) and piperidine (0.081 g,0.95 mmol) were dissolved in DMF (30 ml), and the mixture was stirred at70° C. for 18 hrs. The reaction mixture was combined with ethyl acetateand water. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated, and theresidue was recrystallized from n-hexane-ethyl acetate to give thetitled compound (0.16 g, 54%) as pale yellow crystals.

mp. 162.0-163.0° C.

¹H-NMR (CDCl₃) δ: 1.65-1.62 (6H, m), 2.53-2.55 (4H, m), 3.78 (2H, s),7.60-7.74 (4H, m), 7.86 (1H, t, J=7.7 Hz), 8.40 (1H, d, J=7.7 Hz),8.54-8.56 (1H, m).

IR(KBr): 1660, 1589, 1572, 1531, 1439, 1300, 1277, 1234, 1095, 993, 744cm⁻¹.

Elemental Analysis for C₁₉H₁₉N₃OS

Calcd. C, 67.63; H, 5.68; N, 12.45.

Found C, 67.61; H, 5.72; N, 12.45.

Example 267

2-{6-[(4-Phenyl-1-piperidyl)methyl]-2-pyridyl}-4H-1,3-benzothiazine-4-one

6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl methanesulfonate (0.30 g,0.86 mmol), triethylamine (0.20 ml, 1.42 mmol) and 4-phenylpiperidine(0.15 g, 0.95 mmol) were dissolved in DMF (30 ml), and the mixture wasstirred at 70° C. for 18 hrs. The reaction mixture was combined withethylacetate and water. The organic layer was washed with saturatedbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated, and the residue was recrystallized from n-hexane-ethylacetate to give the titled compound (0.16 g, 76%) as pale yellowcrystals.

mp. 207.0-208.0° C.

¹H-NMR (CDCl₃) δ: 1.83-1.89 (4H, m), 2.27-2.36 (2H, m), 3.10 (2H, d,J=11.5 Hz), 3.86 (2H, s), 7.18-7.31 (5H, m) 7.62-7.68 (3H, m), 7.75 (1H,d, J=7.8 Hz), 7.88 (1H, t, J=7.7 Hz), 8.42 (1H, d, J=7.7 Hz),8.54-8.57(1H, m).

IR(KBr): 1662, 1589, 1570, 1533, 1439, 1289, 1095, 993, 744 cm⁻¹.

Elemental Analysis for C₂₅H₂₃N₃OS

Calcd. C, 72.61; H, 5.61; N, 10.16.

Found C, 72.55; H, 5.60; N, 10.10.

Example 268

2-{6-[(4-Benzyl-1-piperidyl)methyl]-2-pyridyl}-4H-1,3-benzothiazine-4-one

6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl methanesulfonate (0.30 g,0.86 mmol), triethylamine (0.20 ml, 1.42 mmol) and 4-benzylpiperidine(0.17 g, 0.95 mmol) were dissolved in DMF (30 ml), and the mixture wasstirred at 70° C. for 18 hrs. The reaction mixture was combined withethyl acetate and water. The organic layer was washed with saturatedbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated, and the residue was recrystallized from n-hexane-ethylacetate to give the titled compound (0.25 g, 67%) as pale yellowcrystals.

mp. 151.0-153.0° C.

¹H-NMR (CDCl₃) δ: 2.04-2.15 (2H, m), 2.56 (2H, d, J=6.7 Hz), 2.94(2H, d,J=11.1 Hz), 3.77 (2H, s), 7.13-7.29 (5H, m), 7.59-7.71 (4H, m), 7.85(1H, t, J=7.8 Hz), 8.39 (1H, d, J=7.7 Hz), 8.54 (1H, d, J=8.5 Hz).

IR(KBr): 1660, 1589, 1572, 1537, 1439, 1296, 1097, 910, 736 cm⁻¹.

Elemental Analysis for C₂₆H₂₅N₃OS

Calcd. C, 73.04; H, 5.89; N, 9.83.

Found C, 72.87; H, 5.94; N, 9.79.

Example 269

2-(6-{[4-(4-Chlorophenyl)-4-hydroxy-1-piperidyl]methyl}-2-pyridyl)-4H-1,3-benzothiazine-4-one

6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl methanesulfonate (0.30 g,0.86 mmol), triethylamine (0.20 ml, 1.42 mmol) and4-(4-chlorophenyl)-4-hydroxypiperidine (0.20 g, 0.95 mmol) weredissolved in DMF (30 ml), and the mixture was stirred at 70° C. for 18hrs. The reaction mixture was combined with ethyl acetate and water. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated, and the residue wasrecrystallized from n-hexane-ethylacetate to give the titled compound(0.20 g, 49%) as pale yellow crystals.

mp. 151.0-153.0° C.

¹H-NMR (CDCl₃) δ: 1.75-1.79 (2H, m), 2.14-2.24 (2H, m), 2.66-2.73 (2H,m), 2.87-2.95 (2H, m), 3.89 (2H, s), 7.33 (2H, d, J=8.6 Hz), 7.47 (2H,d, J=8.6 Hz), 7.60-7.75 (4H, m), 7.88 (1H, t, J=7.8 Hz), 8.42 (1H, d,J=7.7 Hz), 8.53-8.57 (1H, m).

IR(KBr): 1651, 1572, 1537, 1439, 1302, 1097, 910, 734 cm⁻¹.

Elemental Analysis for C₂₅H₂₂ClN₃O₂S

Calcd. C, 64.72; H, 4.78; N, 9.06.

Found C, 64.43; H, 4.74; N, 8.86.

Reference Example 97

2-Cyano-6-(2-pyrimidinyl)thiopyridine

2-Mercaptopyridine (0.89 g, 7.94 mmol) and sodium hydride (60% in oil,0.35 g, 8.66 mmol) were dissolved in DMF (30 ml), and2-chloro-6-cyanopyridine (1.05 g, 3.00 mmol) was added thereto. Thereaction mixture was stirred at 70° C. for 18 hrs and combined withethyl acetate and water. The organic layer was washed with saturatedbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated, and the residue was recrystallized from n-hexane-ethylacetate to give the titled compound (1.32 g, 85%).

¹H-NMR (CDCl₃) δ: 7.10 (1H, t, J=4.8 Hz), 7.63-7.66 (1H, m), 8.85 (1H,t, J=4.8 Hz), 8.05-8.08 (1H, m), 8.56 (1H, d, J=4.8 Hz).

IR(KBr): 2231, 1572, 1550, 1433, 1371, 1167, 1147, 1086, 983, 798 cm⁻¹.

Example 270

2-[6-(2-Pyrimidinylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-one

2-Cyano-6-(2-pyrimidinyl)thiopyridine (1.30 g, 6.07 mmol) and methylthiosalicylate (1.53 g, 9.10 mmol) were dissolved in toluene (100 ml),and triethylamine (1.70 ml, 12.1 mmol) was added thereto. The mixturewas refluxed for 18 hrs. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the titled compound (0.11 g, 5%) aspale yellow crystals.

mp. 245.2-245.8° C.

¹H-NMR (CDCl₃) δ: 7.10 (1H, t, J=4.8 Hz), 7.60-7.66 (3H, m), 8.93 (1H,t, J=7.8 Hz), 8.03-8.06 (1H, m), 8.49-8.59 (4H, m)

IR(KBr): 1666, 1554, 1535, 1431, 1383, 1296, 1095, 1062, 802, 746 cm⁻¹.

Elemental Analysis for C₁₇H₁₀N₄OS₂

Calcd. C, 58.27; H, 2.88; N, 15.99.

Found C, 58.28; H, 3.09; N, 15.85.

Reference Example 98

2-Cyano-6-(1-methyl-1H-imidazol-2-yl)thiopyridine

2-Mercapto-1-methyl-1H-imidazole (0.91 g, 7.94 mmol) and sodium hydride(60% in oil, 0.35 g, 8.66 mmol) were dissolved in DMF (30 ml), and2-chloro-6-cyanopyridine (1.05 g, 3.00 mmol) was added thereto. Thereaction mixture was stirred at 70° C. for 18 hrs and combined withethyl acetate and water. The organic layer was washed with saturatedbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated, and the residue was recrystallized from n-hexane-ethylacetate to give the titled compound (1.71 g, ca. 100%) as pale yellowcrystals.

¹H-NMR (CDCl₃) δ: 3.79 (3H, s), 7.21-7.23 (1H, m), 7.63-7.66 (1H, m),8.85 (1H, t, J=4.8 Hz), 8.25 (1H, d, J=7.6 Hz), 8.56 (1H, d, J=4.8 Hz).

IR(KBr): 2231, 1570, 1550, 1433, 1373, 1167, 1152, 1086, 983, 798 cm⁻¹.

Example 271

2-{6-[(1-Methyl-1H-imidazol-2-yl)thio]-2-pyridyl}-4H-1,3-benzothiazine-4-one

2-Cyano-6-(1-methyl-1H-imidazol-2-yl)thiopyridine (1.56 g, 7.22 mmol)and methyl thiosalicylate (1.53 g, 9.10 mmol) were dissolved in toluene(100 ml), and triethylamine (1.70 ml, 12.1 mmol) was added thereto. Thereaction mixture was refluxed for 18 hrs. The solvent was evaporated,and the residue was recrystallized from ethanol to give the titledcompound (0.14 g, 5%) as pale yellow crystals.

mp. 171.9-172.3° C.

¹H-NMR (CDCl₃) δ: 3.79 (3H, s), 7.22-7.29 (2H, m), 7.34 (1H, s),7.53-7.55 (1H, m), 7.60-7.76 (3H, m), 8.25 (1H, d, J=7.6 Hz), 8.53 (1H,d, J=1.6 Hz).

IR(KBr): 1658, 1556, 1537, 1433, 1296, 1095, 964, 746 cm⁻¹.

Elemental Analysis for C₁₇H₁₂N₄OS₂

Calcd. C, 57.93; H, 3.43; N, 15.90.

Found C, 58.18; H, 3.10; N, 15.75.

Example 272

2-{6-[(2-Pyridylthio)methyl]-2-pyridyl}-4H-1,3-benzothiazin e-4-one

2-mercaptopyridine (0.21 g, 1.89 mmol) and sodium hydride (60% in oil,0.083 g, 2.06 mmol) were dissolved in DMF (30 ml), and6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl methanesulfonate (0.60 g,1.72 mmol) was added thereto. The reaction mixture was stirred at roomtemperature for 18 hrs and combined with ethyl acetate and water. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the titled compound (0.54 g, 87%) aspale yellow crystals.

mp. 151.3-151.9° C.

¹H-NMR (CDCl₃) δ: 4.70 (2H, s), 6.99-7.03 (1H, m), 7.25-7.28 (1H, m),7.48-7.53 (1H, m), 7.59-7.70 (4H, m), 7.80 (1H, d, J=7.5 Hz), 8.46 (1H,d, J=4.1 Hz), 8.47-8.55 (1H, m).

IR(KBr): 1660, 1589, 1574, 1537, 1452, 1439, 1300, 1097, 993, 744 cm⁻¹.

Elemental Analysis for C₁₉H₁₃N₃OS₂

Calcd. C, 62.79; H, 3.61; N, 11.56.

Found C, 62.87; H, 3.43; N, 11.46.

Example 273

2-{6-[(4-pyridylthio)methyl]-2-pyridyl}-4H-1,3-benzothiazin e-4-one

4-Mercaptopyridine (0.21 g, 1.89 mmol) and sodium hydride (60% in oil,0.083 g, 2.06 mmol) were dissolved in DMF (30 ml), and6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl methanesulfonate (0.60 g,1.72 mmol) was added thereto. The reaction mixture was stirred at roomtemperature for 18 hrs and combined with ethyl acetate and water. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the titled compound (0.11 g, 17%) aspale yellow crystals.

mp. 181.9-182.5° C.

¹H-NMR (CDCl₃) δ: 4.45 (2H, s), 7.31-7.33 (2H, m), 7.61-7.71 (4H, m),7.89 (1H, t, J=7.7 Hz), 8.41-8.45 (3H, s), 8.54-8.56 (1H, m).

IR(KBr): 1658, 1572, 1535, 1452, 1439, 1300, 1095, 993, 742 cm⁻¹.

Elemental Analysis for C₁₉H₁₃N₃OS₂

Calcd. C, 62.79; H, 3.61; N, 11.56.

Found C, 62.89; H, 3.50; N, 11.44.

Reference Example 99

2-Cyano-6-(4-pyridylthio)pyridine

4-Mercaptopyridine (0.88 g, 7.94 mmol) and sodium hydride (60% in oil,0.35 g, 8.66 mmol) were dissolved in THF (30 ml), and the mixture wasstirred at room temperature for 1 hr. A solution of2-chloro-6-cyanopyridine (1.00 g, 7.22 mmol) in THF (10 ml) was added tothe mixture, and the mixture was stirred at room temperature for 18 hrs.The mixture was combined with ethyl acetate and water. The organic layerwas washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated to give the titled compound (1.54 g,ca. 100%) as an oil.

¹H-NMR (CDCl₃) δ: 7.63-7.68 (2H, m), 7.82(1H, t, J=7.5 Hz), 8.36 (1H, d,J=7.7 Hz), 8.55-8.68 (3H, m).

IR(KBr): 2237, 1556, 1427, 1271, 1138, 983, 800 cm⁻¹.

Example 274

2-[6-(4-Pyridylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-one

2-Cyano-6-(4-pyridylthio)pyridine (1.54 g, 7.22 mmol) and methylthiosalicylate (1.34 g, 7.94 mmol) were dissolved in toluene (50 ml),and triethylamine (1.52 ml, 10.83 mmol) was added thereto. The mixturewas refluxed for 18 hrs. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the titled compound (0.053 g, 2%) aspale yellow crystals.

mp. 245.2-245.8° C.

¹H-NMR (CDCl₃) δ: 7.49-7.54 (4H, m), 7.62-7.68 (2H, m), 7.82 (1H, t,J=7.5 Hz), 8.36 (1H, d, J=7.7 Hz), 8.54 (1H, d, J=7.7 Hz), 8.55-8.68(2H, m).

IR(KBr): 1664, 1568, 1531, 1427, 1294, 1157, 1095, 794 cm⁻¹.

Elemental Analysis for C₁₉H₁₈N₂O₃S₂ 0.25H₂O

Calcd. C, 61.08; H, 3.27; N, 11.87.

Found C, 60.87; H, 3.31; N, 11.90.

Reference Example 100

(6-Cyano-2-pyridyl)thioacetic acid

A mixture of thioglycolic acid (6.91 g, 75.0 mmol), sodium hydride (60%in oil, 6.00 g, 150.0 mmol) and DMF (100 ml) was stirred at roomtemperature for 1 hr. 2-Chloro-6-cyanopyridine (7.00 g, 50.0 mmol) wasadded thereto, and the mixture was stirred at room temperature for 18hrs. The reaction mixture was combined with ethyl acetate and 10%hydrochloric acid. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated togive the titled compound (4.56 g, 47%) as pale yellow crystals.

¹H-NMR (CDCl₃) δ: 3.95 (2H, s), 7.38-7.43 (2H, m), 7.61 (1H, t, J=7.9Hz), 12.84 (1H, br s).

IR(KBr): 3152, 2235, 1730, 1572, 1554, 1433, 1141, 746 cm⁻¹.

Reference Example 101

tert-Butyl (6-cyano-2-pyridyl)thioacetate

(6-Cyano-2-pyridyl)thioacetic acid (4.56 g, 23.5 mmol) and concentratedsulfuric acid (1 ml) were added to dichloromethane (300 ml), andisobutene was added thereto. The reaction mixture was sealed and stirredat room temperature for 18 hrs. Water was added to the reaction mixture.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate. The solvent was evaporated to give the titledcompound (5.77 g, 98%) as a pale yellow oil.

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 3.95 (2H, s), 7.38-7.43(2H, m), 7.61(1H, t, J=7.9 Hz).

IR(KBr): 2235, 1732, 1572, 1554, 1433, 1141, 746 cm⁻¹.

Example 275

tert-Butyl [{6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]thio}acetate

tert-Butyl (6-cyano-2-pyridyl)thioacetate (3.00 g, 10.2 mmol) and methylthiosalicylate (2.02 g, 12.0 mmol) were dissolved in toluene (50 ml),and triethylamine (2.52 ml, 18.0 mmol) was added thereto. The mixturewas refluxed for 18 hrs. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the titled compound (2.02 g, 52%) aspale yellow crystals.

mp. 169.5-170.0° C.

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 4.09 (2H, s), 7.44-7.47 (1H, m),7.61-7.74 (4H, m), 8.23-8.26 (1H, m), 8.54-8.57 (1H, m).

IR(KBr): 1730, 1660, 1570, 1573, 1433, 1367, 1296, 1234, 1095, 744 cm⁻¹.

Elemental Analysis for C₁₉H₁₈N₂O₃S₂

Calcd. C, 59.05; H, 4.69; N, 7.25.

Found C, 59.18; H, 4.86; N, 6.98.

Example 276

[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]thioacetic acid

tert-Butyl {[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]thio}acetate(0.30 g, 0.78 mmol) was dissolved in trifluoroacetic acid (5 ml), andthe mixture was stirred for 0.5 hr. Diisopropyl ether was added to themixture. The obtained precipitates were recrystallized from ethanol togive the titled compound (0.21 g, 83%) as pale yellow crystals.

mp. 258.0-260.0° C.

¹H-NMR (DMSO-d₆) δ: 4.41 (2H, s), 7.70-7.75 (2H, m), 7.86 (2H, d, J=3.8Hz), 7.95 (1H, t, J=7.7 Hz), 8.08 (1H, d, J=7.6 Hz), 8.37 (1H, d, J=7.9Hz), 12.88 (1H, br s).

IR(KBr): 3152, 1732, 1633, 1568, 1525, 1433, 1315, 1246, 1211, 985, 748cm⁻¹.

Elemental Analysis for C₁₅H₁₀N₂O₃S₂

Calcd. C, 54.53; H, 3.05; N, 8.48.

Found C, 54.52; H, 2.79; N, 8.18.

Example 277

Ethyl {[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]thio}acetate

Ethyl (6-cyano-2-pyridyl)thioacetate (0.48 g, 2.15 mmol) and methylthiosalicylate (0.40 g, 2.34 mmol) were dissolved in toluene (50 ml),and triethylamine (0.51 ml, 3.66 mmol) was added thereto. The mixturewas refluxed for 18 hrs. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the titled compound (0.40 g, 52%) aspale yellow crystals.

mp. 124.5-125.0° C.

¹H-NMR (CDCl₃) δ: 1.29 (3H, t, J=7.1 Hz), 4.14 (2H, s), 4.25 (2H, q,J=7.1 Hz), 7.45-7.48 (1H, m), 7.60-7.75 (4H, m), 8.23-8.26 (1H, m),8.55-8.57 (1H, m).

IR(KBr): 1736, 1655, 1570, 1533, 1431, 1294, 1143, 1095, 1028, 746 cm⁻¹.

Elemental Analysis for C₁₇H₁₄N₂O₃S₂

Calcd. C, 56.96; H, 3.94; N, 7.82.

Found C, 56.87; H, 3.90; N, 7.94.

Example 278

tert-Butyl {[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]sulfinyl}acetate

tert-Butyl {[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]thio}acetate(0.34 g, 1.00 mmol) was dissolved in chloroform (20 ml), and a solutionof 3-chloroperbenzoic acid (ca. 77%, 0.23 g, 1.00 mmol) in chloroform(10 ml) was added thereto. The mixture was stirred at room temperaturefor 1 hr. The solvent was evaporated, and the residue was recrystallizedfrom n-hexane-ethyl acetate to give the titled compound (0.30 g, 75%) aspale yellow crystals.

mp. 158.8-159.1° C.

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 3.89, 4.17 (2H, q_(AB), J=14.0 Hz),7.63-7.73 (3H, m), 8.19 (1H, t, J=7.8 Hz), 8.26-8.28 (1H, m), 8.55-8.64(2H, m).

IR(KBr): 1724, 1664, 1572, 1537, 1437, 1369, 1298, 1248, 1095, 734 cm⁻¹.

Elemental Analysis for C₁₉H₁₈N₂O₄S₂

Calcd. C, 56.70; H, 4.51; N, 6.96.

Found C, 56.40; H, 4.33; N, 6.79.

Example 279

[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]sulfinylaceti c acid

tert-Butyl [[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]sulfinyl]acetate (0.12 g, 0.30 mmol) was dissolved in trifluoroacetic acid (5 ml),and the mixture was stirred for 0.5 hr. Diisopropyl ether was added tothe mixture. The obtained crystals were recrystallized from ethanol togive the titled compound (0.081 g, 79%) as pale yellow crystals.

mp. 186.5-188.0° C.

¹H-NMR (DMSO-d₆) δ: 4.02, 4.23 (2H, q_(AB), J=14.5 Hz), 7.73 (1H, t,J=7.7 Hz), 7.84 (1H, t, J=7.9 Hz), 7.94 (1H, d, J=7.8 Hz), 8.23 (1H, d,J=7.3 Hz), 8.34-8.47 (2H, m), 13.38 (1H, br s).

IR(KBr): 2850, 1722, 1658, 1570, 1529, 1437, 1288, 1236, 1184, 1095, 734cm⁻¹.

Elemental Analysis for C₁₅H₁₀N₂O₄S₂

Calcd. C, 52.01; H, 2.91; N, 8.09.

Found C, 51.85; H, 2.96; N, 8.02.

Example 280

tert-Butyl {[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]sulfonyl}acetate

tert-Butyl {[6-(4-oxo-4H-1,3-benzothiazin-2-yl)₂-pyridyl]thio}acetate(1.00 g, 2.59 mmol) was dissolved in chloroform (50 ml), and a solutionof 3-chloroperbenzoic acid (ca. 77%, 1.16 g, 5.18 mmol) in chloroform(10 ml) was added to thereto. The mixture was stirred at roomtemperature for 3 hrs. The solvent was evaporated, and the residue wasrecrystallized from n-hexane-ethyl acetate to give the titled compound(0.13 g, 12%) as pale yellow crystals.

mp. 159.0-160.0° C.

¹H-NMR (CDCl₃) δ: 1.30 (9H, s), 4.54 (2H, s), 7.66-7.75 (4H, m), 8.23(1H, t, J=7.8 Hz), 8.30-8.33 (1H, m), 8.56-8.59 (1H, m), 8.77-8.80 (1H,m).

IR(KBr): 1726, 1662, 1570, 1535, 1439, 1332, 1300, 1170, 1095, 733 cm⁻¹.

Elemental Analysis for C₁₉H₁₈N₂O₅S₂

Calcd. C, 54.53; H, 4.34; N, 6.69.

Found C, 54.36; H, 4.29; N, 6.65.

Example 281

[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]sulfonylaceti c acid

tert-Butyl {[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]sulfonyl}acetate (0.10 g, 0.24 mmol) was dissolved in trifluoroacetic acid (5 ml),and the mixture was stirred f or 0.5 hr. Diisopropyl ether was added tothe mixture. The obtained precipitates were recrystallized from ethanolto give the titled compound (0.048 g, 55%) as pale yellow crystals.

mp. 192.0-193.5° C.

¹H-NMR (DMSO-d₆) δ: 4.80 (2H, s), 7.77 (1H, t, J=7.4 Hz), 7.85 (1H, t,J=7.5 Hz), 8.00 (1H, d, J=7.9 Hz), 8.39 (2H, d, J=7.8 Hz), 8.47 (1H, t,J=7.8 Hz), 8.65 (1H, t, J=7.7 Hz), 13.49 (1H, br s).

IR(KBr): 3071, 1739, 1655, 1572, 1537, 1440, 1340, 1315, 1180, 1095, 733cm⁻¹.

Elemental Analysis for C₁₅H₁₀N₂O₅S₂

Calcd. C, 49.72; H, 2.78; N, 7.73.

Found C, 49.52; H, 2.83; N, 7.55.

Reference Example 102

(6-Cyano-2-pyridyl) thioacetamide

A mixture of (6-cyano-2-pyridyl)thioacetic acid (0.95 g, 4.89 mmol),isobutyl chloroformate (1.05 ml, 7.33 mmol), triethylamine (1.03 ml,7.33 mmol) and THF (150 ml) was stirred under ice cooling condition for2 hrs. 28% ammonium solution (100 ml) was added to the mixture, and themixture was stirred under ice cooling condition for 2 hrs. The reactionmixture was combined with ethyl acetate. The organic layer was washedwith saturated brine and dried over magnesium sulfate. The solvent wasevaporated to give the titled compound (0.49 g, 52%) as pale yellowcrystals

¹H-NMR (CDCl₃) δ: 3.85 (2H, s), 5.44(1H, br s), 6.54(1H, br s),7.43-7.47(2H, m), 7.64-7.69 (1H, m), 12.84(1H, br s).

IR(KBr): 3385, 3171, 2231, 1647, 1572, 1545, 1425, 1145, 796 cm⁻¹.

Example 282

2-[[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]thioacetam ide

(6-Cyano-2-pyridyl)thioacetamide (0.47 g, 2.43 mmol) and methylthiosalicylate (0.45 g, 2.67 mmol) were dissolved in toluene (50 ml),and triethylamine (0.51 ml, 3.64 mmol) was added thereto. The mixturewas refluxed for 18 hrs. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the titled compound (0.33 g, 41%) aswhite crystals.

mp. 256.7-257.0° C.

¹H-NMR (DMSO-d₆) δ: 4.00 (2H, s), 7.26(1H, br s), 7.68-7.77 (3H, m),7.83-7.97 (3H, m), 8.06 (1H, d, J=6.0 Hz), 8.36 (1H, d, J=7.9 Hz).

IR(KBr): 3379, 3173, 1666, 1633, 1570, 1535, 1435, 1367, 1302, 1248,1095, 752 cm⁻¹.

Elemental Analysis for C₁₅H₁₁N₃O₂S₂

Calcd. C, 54.69; H, 3.37; N, 12.76.

Found C, 54.63; H, 3.27; N, 12.71.

Example 283

2-{[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]sulfinyl}a cetamide

2-{[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]thio }acetamide (0.12g, 0.36 mmol) was dissolved in chloroform (300 ml), and a solution of3-chloroperbenzoic acid (77%, 0.082 g, 0.36 mmol) in chloroform (10 ml)was added dropwise thereto. The mixture was stirred at room temperaturefor 1 hr. The solvent was evaporated, and the residue was recrystallizedfrom ethanol to give the titled compound (0.071 g, 57%) as whitecrystals.

¹H-NMR (DMSO-d₆) δ: 3.82, 4.03 (2H, q_(AB), J=13.8 Hz), 7.47 (1H, br s),7.75 (2H, t, J=7.8 Hz), 7.86 (1H, t, J=7.1 Hz), 7.98 (1H, d, J=7.9 Hz),8.23 (1H, d, J=7.5 Hz), 8.36-8.48 (3H, m).

IR(KBr): 3360, 1685, 1647, 1570, 1529, 1439, 1307, 1298, 1246, 1099, 746cm⁻¹.

Elemental Analysis for C₁₅H₁₁N₃O₃S₂ 0.25H₂O

Calcd. C, 51.49; H, 3.31; N, 12.01.

Found C, 51.53; H, 3.06; N, 11.85.

Reference Example 103

6-Cyano-2-methylthiopyrimidine

A mixture of 2-chloro-6-cyanopyrimidine (2.20 g, 15.8 mmol), sodiumthiomethoxide (1.22 g, 17.3 mmol) and THF (100 ml) was refluxed for 2hrs. The reaction mixture was combined with ethyl acetate and water. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated to give the titledcompound (1.57 g, 66%) as pale yellow crystals.

¹H-NMR (CDCl₃) δ: 2.58 (3H, s), 7.26(1H, d, J=4.8 Hz), 8.70 (1H, d,J=4.8 Hz).

IR(KBr): 2241, 1554, 1537, 1396, 1348, 1197, 862 cm⁻¹.

Example 284

2-[2-(Methylthio)-6-pyrimidinyl]-4H-1,3-benzothiazine-4-one

6-Cyano-2-methylthiopyrimidine (1.37 g, 9.06 mmol) and methylthiosalicylate (3.05 g, 18.1 mmol) were dissolved in toluene (30 ml),and triethylamine (3.80 ml, 27.2 mmol) was added thereto. The mixturewas refluxed for 18 hrs. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the titled compound (1.40 g, 54%) aspale yellow crystals.

mp. 223.5-224.0° C.

¹H-NMR (CDCl₃) δ: 2.70 (3H, s), 7.62-7.76 (3H, m), 8.03(1H, d, J=5.0Hz), 8.54-8.57 (1H, m), 8.78 (1H, d, J=5.0 Hz).

IR(KBr): 1655, 1533, 1412, 1346, 1284, 1203, 1093, 748 cm⁻¹.

Elemental Analysis for C₁₃H₉N₃OS₂

Calcd. C, 54.34; H, 3.16; N, 14.62.

Found C, 54.57; H, 3.27; N, 14.76.

Example 285

2-[2-(Methylsulfinyl)-6-pyrimidinyl]-4H-1,3-benzothiazine-4-one

2-[2-(Methylthio)-6-pyrimidinyl]-4H-1,3-benzothiazine -4-one (0.30 g,1.50 mmol) was dissolved in chloroform (100 ml), and a solution of3-chloroperbenzoic acid (ca. 77%, 0.23 g, 1.50 mmol) in chloroform (10ml) was added dropwise thereto. The mixture was stirred at roomtemperature for 1 hr. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the titled compound (0.18 g, 55%) aspale yellow crystals.

mp. 250.5-252.0° C.

¹H-NMR (CDCl₃) δ: ¹H-NMR (CDCl₃) δ: 3.08 (3H, s), 7.65-7.79 (3H, m),8.50(1H, d, J=5.0 Hz), 8.56-8.59 (1H, m), 9.16 (1H, d, J=5.0 Hz).

IR(KBr): 1664, 1566, 1535, 1439, 1377, 1292, 1062, 729 cm⁻¹.

Elemental Analysis for C₁₃H₉N₃O₂S₂

Calcd. C, 51.47; H, 2.99; N, 13.85.

Found C, 51.45; H, 3.06; N, 13.87.

Example 286

2-[2-(Methylsulfonyl)-6-pyrimidinyl]-4H-1,3-benzothiazine-4-one

2-[2-(Methylthio)-6-pyrimidinyl]-4H-1,3-benzothiazine -4-one (0.30 g,1.05 mmol) was dissolved in chloroform (50 ml), and a solution of3-chloroperbenzoic acid (ca. 77%, 0.47 g, 2.10 mmol) in chloroform (10ml) was added dropwise thereto. The mixture was stirred at roomtemperature for 3 hrs. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the titled compound (0.030 g, 9%) aspale yellow crystals.

mp. 269.5-270.0° C.

¹H-NMR (CDCl₃) δ: ¹H-NMR (CDCl₃) δ: 3.49 (3H, s), 7.66-7.80 (3H, m),8.57-8.60 (1H, m), 8.64(1H, d, J=5.2 Hz), 9.20 (1H, d, J=5.2 Hz).

IR(KBr): 1662, 1570, 1539, 1425, 1307, 1290, 1140, 1060, 993, 758 cm⁻¹.

Elemental Analysis for C₁₃H₉N₃O₃S₂

Calcd. C, 48.89; H, 2.84; N, 13.16.

Found C, 48.68; H, 2.77; N, 13.01.

Reference Example 104

2-Cyano-6-methylthiopyrazine

A mixture of 2-chloro-6-cyanopyrazine (1.40 g, 10.0 mmol) sodiumthiomethoxide (0.78 g, 11.0 mmol) and THF (100 ml) was refluxed for 2hrs. The reaction mixture was combined with ethyl acetate and water. Theorganic layer was washed with saturated brine and dried over magnesiumsulfate. The solvent was evaporated to give the titled compound (1.25 g,83%) as pale yellow crystals.

¹H-NMR (CDCl₃) δ: 2.61 (3H, s), 8.49 (1H, s), 8.60 (1H, s)

IR(KBr): 2241, 1670, 1521, 1390, 1190, 1167, 1138, 1108, 887, 734 cm⁻¹.

Example 287

2-[6-(Methylthio)-2-pyrazinyl]-4H-1,3-benzothiazine-4-one

2-Cyano-6-methylthiopyrazine (0.80 g, 5.29 mmol) and methylthiosalicylate (1.34 g, 7.94 mmol) were dissolved in toluene (100 ml),and triethylamine (1.48 ml, 10.6 mmol) was added thereto. The mixturewas refluxed for 18 hrs. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the tilted compound (0.35 g, 23%) aspale yellow crystals.

mp. 202.4-202.9° C.

¹H-NMR (CDCl₃) δ: 2.73 (3H, s), 7.60-7.74 (3H, m), 8.55-8.58 (1H, m),8.67 (1H, s), 9.29 (1H, s).

IR(KBr): 1649, 1570, 1527, 1439, 1292, 1124, 1095, 1062, 1003, 916, 733cm⁻¹.

Elemental Analysis for C₁₃H₉N₃OS₂

Calcd. C, 54.34; H, 3.16; N, 14.62.

Found C, 54.28; H, 3.09; N, 14.55.

Example 288

2-[6-(Methylsulfinyl)-2-pyrazinyl]-4H-1,3-benzothiazine-4-o ne

2-[6-(Methylthio)-2-pyrazinyl]-4H-1,3-benzothiazine-4-one (0.14 g, 0.50mmol) was dissolved in chloroform (50 ml), and a solution of3-chloroperbenzoic acid (ca. 77%, 0.11 g, 0.50 mmol) was added dropwisethereto. The mixture was stirred at room temperature for 1 hr. Thesolvent was evaporated, and the residue was recrystallized from ethanolto give the titled compound (0.12 g, 79%) as pale yellow crystals.

mp. 228.5-230.5° C.

¹H-NMR (CDCl₃) δ: 3.06 (3H, s), 7.60-7.63 (1H, m), 7.67-7.78 (2H, m),8.56-8.59 (1H, m), 9.47 (1H, s), 9.81 (1H, s).

IR(KBr): 1658, 1570, 1529, 1288, 1059, 1010, 968, 736 cm⁻¹.

Elemental Analysis for C₁₃H₉N₃O₂S₂

Calcd. C, 51.47; H, 2.99; N, 13.85.

Found C, 51.33; H, 3.04; N, 13.95.

Example 289

2-[6-(Methylsulfonyl)-2-pyrazinyl]-4H-1,3-benzothiazine-4-o ne

2-[6-(Methylthio)-2-pyrazinyl]-4H-1,3-benzothiazine-4-one (0.14 g, 1.0mmol) was dissolved in chloroform (30 ml), and a solution of3-chloroperbenzoic acid (ca. 77%, 0.22 g, 0.66 mmol) was added dropwisethereto. The mixture was stirred at room temperature for 3 hr. Thesolvent was evaporated, and the residue was recrystallized from ethanolto give the titled compound (0.040 g, 25%) as pale yellow crystals.

mp. 232.0-233.0° C.

¹H-NMR (CDCl₃) δ: 3.40 (3H, s), 7.63-7.80 (3H, m), 8.57-8.60 (1H, m),9.52 (1H, s), 9.96 (1H, s).

IR(KBr): 1660, 1572, 1531, 1331, 1290, 1091, 1014, 978, 740 cm⁻¹.

Elemental Analysis for C₁₃H₉N₃O₃S₂

Calcd. C, 48.89; H, 2.84; N, 13.16.

Found C, 48.83; H, 2.78; N, 13.29.

Reference Example 105

2-Cyano-6-dimethylaminopyrazine

2-Chloro-6-cyanopyrazine (0.85 g, 6.09 mmol) and 1.67 N dimethylamine inacetonitrile (4.00 ml, 6.70 mmol) were added to THF (100 ml), and themixture was stirred at room temperature for 2 hrs. The reaction mixturewas combined with ethyl acetate and water. The organic layer was washedwith saturated brine and dried over anhydrous magnesium sulfate. Thesolvent was evaporated to give the titled compound (0.50 g, 55%) as paleyellow crystals.

¹H-NMR (CDCl₃) δ: 3.16 (6H, s), 8.07 (1H, s), 8.18 (1H, s)

IR(KBr): 2233, 1738, 1680, 1591, 1521, 1367, 1242, 1150, 993, 846 cm⁻¹.

Example 290

2-[6-(Dimethylamino)-2-pyrazinyl]-4H-1,3-benzothiazine-4-on e

2-Cyano-6-dimethylaminopyrazine (0.50 g, 3.37 mmol) and methylthiosalicylate (1.14 g, 6.75 mmol) was dissolved in toluene (100 ml),and triethylamine (1.42 ml, 10.1 mmol) was added thereto. The mixturewas refluxed for 18 hrs. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the titled compound (0.31 g, 32%) aspale yellow crystals.

mp. 248.0-249.0° C.

¹H-NMR (CDCl₃) δ: 3.25 (6H, s), 7.57-7.68 (3H, m), 8.24 (1H, m),8.53-8.56 (1H, m), 8.90 (1H, s).

IR(KBr): 1657, 1581, 1570, 1537, 1435, 1290, 1236, 1093, 989, 756 cm⁻¹.

Elemental Analysis for C₁₄H₁₂N₄OS

Calcd. C, 59.14; H, 4.25; N, 19.70.

Found C, 59.01; H, 4.17; N, 19.54.

Reference Example 106

tert-Butyl [methyl(6-cyano-2-pyrazinyl)amino]acetate

2-Chloro-6-cyanopyrazine (2.09 g, 15.0 mmol), sarcosine tert-butyl esterhydrochloride salt (2.72 g, 15.0 mmol) and triethylamine (2.38 ml, 17.0mmol) were added to DMF (30 ml), and the mixture was stirred at roomtemperature for 18 hrs. The reaction mixture was combined with ethylacetate and water. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated togive the titled compound (1.00 g, 27%) as pale yellow crystals.

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 3.21 (3H, s), 4.18(2H, s), 8.16 (1H, s),8.23 (1H, s).

IR(KBr): 2233, 1734, 1576, 1521, 1419, 1367, 1226, 1153, 993, 842 cm⁻¹.

Example 291

tert-Butyl {methyl[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyrazinyl]amino}acetate

tert-Butyl [methyl(6-cyano-2-pyrazinyl)amino]acetate (1.00 g, 4.03 mmol)and methyl thiosalicylate (1.36 g, 8.06 mmol) were dissolved in toluene(50 ml), and triethylamine (1.70 ml, 12.1 mmol) was added thereto. Themixture was refluxed for 18 hrs. The solvent was evaporated, and theresidue was recrystallized from ethanol to give the titled compound(0.41 g, 26%) as pale yellow crystals.

mp. 189.0-190.5° C.

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 3.30 (3H, s), 4.29 (2H, s) 7.56-7.71(3H, m), 8.30 (1H, s), 8.55 (1H, d, J=7.6 Hz), 8.99 (1H, s).

IR(KBr): 1736, 1660, 1570, 1537, 1439, 1369, 1294, 1224, 1097, 734 cm⁻¹.

Elemental Analysis for C₁₉H₂₀N₄O₃S

Calcd. C, 59.36; H, 5.24; N, 14.57.

Found C, 59.21; H, 5.13; N, 14.38.

Example 292

{Methyl[6-(4-oxo-1,3-benzothiazin-2-yl)-2-pyrazinyl]amino}a cetic acid

tert-Butyl {methyl[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyrazinyl]amino}acetate (0.20 g, 0.52 mmol) was dissolved in trifluoroacetic acid (5ml), and the mixture was stirred for 0.5 hr. Diisopropyl ether was addedthereto. The obtained precipitates were recrystallized from ethanol togive the titled compound (0.15 g, 87%) as pale yellow crystals

mp. 283.0° C. (decomposed)

¹H-NMR (DMSO-d₆) δ: 3.24 (3H, s), 4.43 (2H, s), 7.70-7.75 (1H, m),7.79-7.88 (2H, m), 8.35 (1H, d, J=7.3 Hz), 8.67 (1H, s) 12.83 (1H, brs).

IR(KBr): 3082, 2513, 1703, 1653, 1587, 1572, 1541, 1435, 1421, 1294,1271, 999, 752 cm⁻¹.

Elemental Analysis for C₁₅H₁₂N₄O₃S

Calcd. C, 54.87; H, 3.68; N, 17.06.

Found C, 54.67; H, 3.54; N, 16.89.

Reference Example 107

tert-Butyl [methyl(6-cyano-2-pyrimidinyl)amino]acetate

2-Chloro-6-cyanopyrimidine (1.45 g, 10.4 mmol), sarcosine tert-butylester hydrochloric acid (1.89 g, 10.4 mmol) and triethylamine (1.60 ml,11.4 mmol) were added to DMF (30 ml), and the mixture was stirred atroom temperature for 18 hrs. The reaction mixture was combined withethyl acetate and water. The organic layer was washed with saturatedbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated to give the titled compound (1.99 g, 77%) as pale yellowcrystals.

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 3.24 (3H, d, J=5.5 Hz), 4.22 (2H, d,J=8.7 Hz), 6.80 (1H, d, J=4.7 Hz), 8.43-8.51 (1H, m).

IR(KBr): 2237, 1736, 1574, 1537, 1410, 1365, 1226, 1153, 1033, 815 cm⁻¹.

Example 293

tert-Butyl {methyl[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyrimidinyl]amino}acetate

tert-Butyl [methyl(6-cyano-2-pyrimidinyl)amino]acetate (1.63 g, 6.56mmol) and methyl thiosalicylate (3.31 g, 19.7 mmol) were dissolved intoluene (50 ml), and triethylamine (2.76 ml, 19.7 mmol) was addedthereto. The mixture was refluxed for 18 hrs. The solvent wasevaporated, and the residue was recrystallized from ethanol to give thetitled compound (1.20 g, 39%) as pale yellow crystals.

mp. 186.5-188.0° C.

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 3.36 (3H, s), 4.33 (2H, s), 7.60-7.73(4H, m), 8.53-8.61 (2H, m).

IR(KBr): 1738, 1660, 1568, 1539, 1408, 1365, 1294, 1209, 1153, 1097, 734cm⁻¹.

Elemental Analysis for C₁₉H₂₀N₄O₃S

Calcd. C, 59.36; H, 5.24; N, 14.57.

Found C, 59.17; H, 5.08; N, 14.39.

Example 294

{Methyl[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyrimidinyl]am ino}aceticacid

tert-Butyl {methyl[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyrimidinyl]amino}acetate (0.20 g, 0.52 mmol) was dissolved in trifluoroacetic acid (5ml), and the mixture was stirred for 0.5 hr. Diisopropyl ether was addedthereto. The obtained crystals were recrystallized from ethanol to givethe titled compound (0.15 g, 87%) as pale yellow crystals.

mp. 215.0° C. (decomposed)

¹H-NMR (DMSO-d₆) δ: 3.27 (3H, d, J=19.4 Hz), 4.40 (2H, d, J=14.6 Hz),7.43 (1H, d, J=4.9 Hz), 7.72-7.77 (1H, m), 7.81-7.93 (2H, m), 8.35 (1H,d, J=7.3 Hz), 8.67-8.72 (1H, m), 12.73 (1H, br s).

IR(KBr): 3082, 2515, 1703, 1653, 1589, 1572, 1541, 1435, 1421, 1294,1271, 752 cm⁻¹.

Elemental Analysis for C₁₅H₁₂N₄O₃S

Calcd. C, 54.87; H, 3.68; N, 17.06.

Found C, 54.61; H, 3.50; N, 16.89.

Reference Example 108

tert-Butyl [(6-cyano-2-pyrimidinyl)amino]acetate

2-Chloro-6-cyanopyrimidine (2.09 g, 15.0 mmol), glycine tert-butyl esterhydrochloride salt (2.52 g, 15.0 mmol) and triethylamine (2.38 ml, 17.0mmol) were dissolved in DMF (30 ml), and the mixture was stirred at roomtemperature for 18 hrs. The reaction mixture was combined with ethylacetate and water. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated togive the titled compound (1.07 g, 45%) as pale yellow crystals.

¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 4.08 (2H, d, J=5.6 Hz), 5.90 (1H, br s),6.88 (1H, d, J=4.7 Hz), 8.46 (1H, d, J=4.7 Hz).

IR(KBr): 3261, 2984, 2243, 1734, 1601, 1570, 1535, 1417, 1367, 1228,1155, 848, 733 cm⁻¹.

Example 295

tert-Butyl {[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyrimidinyl]amino}acetate

tert-Butyl [(6-cyano-2-pyrimidinyl)amino]acetate (1.00 g, 4.03 mmol) andmethyl thiosalicylate (2.34 g, 13.9 mmol) were dissolved in toluene (50ml), and triethylamine (1.95 ml, 13.9 mmol) was added thereto. Themixture was refluxed for 18 hrs. The solvent was evaporated, and theresidue was recrystallized from ethanol to give the titled compound(1.03 g, 60%) as pale yellow crystals.

mp. 247.0-248.0° C.

¹H-NMR (CDCl₃) δ: 1.51 (9H, s), 4.20 (2H, d, J=5.5 Hz), 5.84 (1H, br s),7.61-7.74 (4H, m), 8.53-8.57 (2H, m).

IR(KBr): 3261, 2976, 1741, 1651, 1591, 1568, 1531, 1408, 1219, 1143,1095, 733 cm⁻¹.

Elemental Analysis for C₁₈H₁₈N₄O₃S

Calcd. C, 58.36; H, 4.90; N, 15.12.

Found C, 58.13; H, 4.77; N, 14.98.

Example 296

{[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyrimidinyl]amino}ac etic acid

tert-Butyl {[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyrimidinyl]amino}acetate (0.20 g, 0.54 mmol) was dissolved in trifluoroacetic acid (5 ml),and the mixture was stirred for 0.5 hr. Diisopropyl ether was addedthereto. The obtained precipitates were recrystallized from ethanol togive the titled compound (0.13 g, 75%) as pale yellow crystals

mp. 283.0-284.0° C.

¹H-NMR (DMSO-d₆) δ: 4.04 (2H, d, J=12.3 Hz), 7.43 (1H, d, J=4.8 Hz),7.75 (1H, t, J=6.9 Hz), 7.85 (1H, t, J=7.6 Hz), 7.98 (1H, br s), 8.36(1H, d, J=7.4 Hz), 8.64 (1H, d, J=4.8 Hz), 12.58 (1H, br s).

IR(KBr): 3254, 2995, 2567, 1730, 1705, 1653, 1603, 1568, 1537, 1437,1425, 1398, 1294, 1275, 1095, 823, 752 cm⁻¹.

Elemental Analysis for C₁₄H₁₀N₄O₃S

Calcd. C, 53.50; H, 3.21; N, 17.82.

Found C, 53.67; H, 3.10; N, 17.89.

Reference Example 109

2-Cyano-6-[2-(dimethylamino)ethylthio]pyrazine

2-Dimethylaminoethanethiol hydrochloride salt (1.46 g, 10.0 mmol) andsodium hydride (60% in oil, 0.88 g, 22.0 mmol) were added to THF (50ml), and 2-chloro-6-cyanopyrazine (1.40 g, 10.0 mmol) was added thereto.The mixture was stirred at room temperature for 18 hrs. The reactionmixture was combined with ethyl acetate and water. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated, and the residue was recrystallized fromn-hexane-ethyl acetate to give the titled compound (1.00 g, 48%) as paleyellow crystals.

¹H-NMR (CDCl₃) δ: 2.32 (6H, s), 2.62-2.67 (2H, m), 3.31-3.38 (2H, m),8.48 (1H, s), 8.58 (1H, s).

IR(KBr): 2233, 1576, 1549, 1456, 1143, 794 cm⁻¹.

Example 297

2-(6-{[2-Dimethylamino]ethyl}thio)-2-pyrazinyl]-4H-1,3-benzothiazine-4-one

2-Cyano-6-[2-(dimethylamino)ethylthio]pyrazine (1.00 g, 4.80 mmol) andmethyl thiosalicylate (1.61 g, 9.60 mmol) were dissolved in toluene (50ml), and triethylamine (1.70 ml, 12.0 mmol) was added thereto. Themixture was refluxed for 18 hrs. The solvent was evaporated, and theresidue was recrystallized from ethanol to give the titled compound(0.45 g, 27%) as pale yellow crystals.

mp. 160.5° C. (decomposed)

¹H-NMR (CDCl₃) δ: 2.38 (6H, s), 2.77 (2H, t, J=6.9 Hz), 3.47 (2H, t,J=6.9 Hz) 7.59-7.72 (3H, m), 8.55-8.58 (1H, m), 8.65 (1H, s), 9.29 (1H,s).

IR(KBr): 1655, 1572, 1537, 1435, 1286, 1091, 912, 744 cm⁻¹.

Elemental Analysis for C₁₆H₁₆N₄OS₂

Calcd. C, 55.79; H, 4.68; N, 16.27.

Found C, 55.40; H, 4.50; N, 16.08.

Reference Example 110

4-Chloro-2-cyanopyridine

4-Chloropyridine N-oxide (7.53 g, 58.1 mmol) and N,N-dimethylcarbamoylchloride (9.36 g, 87.0 mmol) were added to acetonitrile (200 ml), andtrimethylsilyl cyanide (11.5 g, 116 mmol) was added dropwise thereto.The mixture was stirred at room temperature for 18 hrs. The reactionmixture was combined with ethyl acetate and water. The organic layer wassuccessively washed with saturated aqueous sodium hydrogen carbonatesolution and saturated brine and dried over magnesium sulfate. Thesolvent was evaporated, and the residue was subjected to a silica gel(200 g) column chromatography. The fractions eluted with n-hexane-ethylacetate (3:1, v/v) were collected, concentrated to give the titledcompound (8.05 g, 99%) as a pale yellow oil.

¹H-NMR (CDCl₃) δ: 7.54-7.56 (1H, m), 7.72(1H, s), 8.63 (1H, d, J=5.3Hz).

IR(KBr): 2239, 1568, 1549, 1462, 1379, 1288, 1215, 844, 704 cm⁻¹.

Reference Example 111

2-Cyano-4-methylthiopyridine

4-Chloro-2-cyanopyridine (2.18 g, 15.7 mmol) and sodium thiomethoxide(2.20 g, 31.4 mmol) were dissolved in THF (100 ml), and the mixture wasrefluxed for 2 hrs. The reaction mixture was combined with ethyl acetateand water. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated to give thetitled compound (2.36 g, 99%) as pale yellow crystals.

¹H-NMR (CDCl₃) δ: 2.53 (3H, s), 7.25-7.27 (1H, m), 7.45(1H, s), 8.46(1H, d, J=5.3 Hz).

IR(KBr): 2233, 1574, 1537, 1462, 1386, 1292, 1099, 987, 962, 844 cm⁻¹.

Example 298

2-[4-(Methylthio)-2-pyridyl)-4H-1,3-benzothiazine-4-one

2-Cyano-4-methylthiopyridine (2.36 g, 15.7 mmol) and methylthiosalicylate (5.28 g, 31.4 mmol) were dissolved in toluene (100 ml),and triethylamine (9.9 ml, 70.7 mmol) was added thereto. The mixture wasrefluxed for 18 hrs. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the titled compound (3.00 g, 68%) aspale yellow crystals.

mp. 213.0-214.0° C.

¹H-NMR (CDCl₃) δ: 2.59 (3H, s), 7.30-7.32 (1H, m), 7.62-7.70 (3H, m),8.34 (1H, s), 8.47-8.49 (1H, m), 8.54-8.55 (1H, m).

IR(KBr): 1651, 1570, 1531, 1456, 1296, 1277, 1255, 1240, 1101, 1066,831, 734 cm⁻¹.

Elemental Analysis for C₁₄H₁₀N₂OS₂

Calcd. C, 58.72; H, 3.52; N, 9.78.

Found C, 58.66; H, 3.39; N, 9.55.

Example 299

2-[4-(Methylsulfinyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one

2-[4-(Methylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-o ne (0.28 g, 1.00mmol) was dissolved in chloroform (50 ml), and a solution of3-chloroperbenzoic acid (ca. 77%, 0.23 g, 1.00 mmol) in chloroform (10ml) was added dropwise thereto. The mixture was stirred at roomtemperature for 1 hrs. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the titled compound (0.23 g, 77%) aspale yellow crystals.

mp. 205.0-206.0° C.

¹H-NMR (CDCl₃) δ: ¹H-NMR (CDCl₃) δ: 2.87 (3H, s), 7.63-7.73 (3H, m),8.04-8.07 (1H, m), 8.58-8.59 (1H, m), 8.96 (1H, d, J=4.9 Hz).

IR(KBr): 1657, 1570, 1529, 1292, 1236, 1062, 1030, 914, 723 cm⁻¹.

Elemental Analysis for C₁₄H₁₀N₂O₂S₂

Calcd. C, 55.61; H, 3.33; N, 9.26.

Found C, 55.55; H, 3.04; N, 9.05.

Example 300

2-[4-(Methylsulfonyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one

2-[4-(Methylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-o ne (0.28 g, 1.00mmol) was dissolved in chloroform (30 ml), and a solution of3-chloroperbenzoic acid (ca. 77%, 0.46 g, 2.00 mmol) in chloroform (10ml) was added dropwise thereto. The mixture was stirred at roomtemperature for 3 hrs. The solvent was evaporated, and the residue wasrecrystallized from ethanol to give the titled compound (0.14 g, 45%) aspale yellow crystals.

mp. 300.0-301.0° C.

¹H-NMR (DMSO-d₆) δ: 3.46 (3H, s), 7.74-7.79 (1H, m), 7.84-7.87 (1H, m),7.84-7.87 (1H, m), 8.27-8.29 (1H, m), 8.38-8.40 (1H, m), 8.71 (1H, s),9.15 (1H, d, J=4.9 Hz).

IR(KBr): 1651, 1570, 1525, 1439, 1296, 1143, 1089, 981, 783 cm⁻¹.

Elemental Analysis for C₁₄H₁₀N₂O₃S₂

Calcd. C, 52.82; H, 3.17; N, 8.80.

Found C, 52.83; H, 3.88; N, 8.56.

Reference Example 112

(3-Pyridyl)propyl acetate

2-Pyridinepropanol (2.0 g, 14.6 mmol) was dissolved in pyridine (5 ml),and acetic anhydride (3.0 g, 29.2 mmol) was added thereto. The reactionmixture was stirred at room temperature for 2.5 hrs, and subjected to asilica gel (75 g) column chromatography. The fractions eluted withhexane-ethyl acetate (3:1, v/v) were collected and concentrated to givethe titled compound (2.6 g, 99%).

¹H-NMR (CDCl₃) δ: 2.03 (3H, s), 2.11 (2H, m), 2.88 (2H, t, J 7.5 Hz),4.12 (2H, t, J=6.3 Hz), 7.11-7.15 (2H, m), 7.61 (1H, t, J=7.8 Hz), 8.54(1H, d, J=5.1 Hz).

Reference Example 113

3-(1-Oxide-2-pyridyl)propyl acetate

(3-Pyridyl)propyl acetate (2.6 g, 14.5 mmol) was dissolved in ethylacetate (15 ml), and 3-chloroperbenzoic acid (ca. 77%, 3.7 g, 15.0 mmol)was added thereto. The reaction mixture was stirred at room temperaturefor 14 hrs and subjected to a silica gel (80 g) column chromatography.The fractions eluted with ethyl acetate-ethanol (3:1, v/v) werecollected and concentrated to give the titled compound (2.8 g, 99%).

¹H-NMR (CDCl₃) δ: 2.05 (3H, s), 2.11 (2H, m), 3.01 (2H, t, J=7.5 Hz),4.15 (2H, t, J=6.3 Hz), 7.13-7.27 (3H, m), 8.25 (1H, d, J=6.0 Hz).

Reference Example 114

3-(6-Cyano-2-pyridyl)propyl acetate

3-(1-Oxide-2-pyridyl)propyl acetate (2.8 g, 14.3 mmol) was dissolved innitroethane (15 ml), and trimethylsilyl cyanide (2.9 g, 28.7 mmol) andN,N-dimethylcarbamoyl chloride (3.1 g, 28.6 mmol) were added thereto.The reaction mixture was stirred at room temperature for 39 hrs andcombined with ethyl acetate and water. The organic layer wassuccessively washed with saturated aqueous sodium hydrogen carbonatesolution and saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated, and the residue was subjected to a silicagel (50 g) column chromatography. The fractions eluted with hexane-ethylacetate (3:1, v/v) were collected and concentrated to give the titledcompound (2.5 g, 86%).

¹H-NMR (CDCl₃) δ: 2.05 (3H, s), 2.11 (2H, m), 2.92 (2H, t, J=7.5 Hz),4.13 (2H, t, J=6.3 Hz), 7.38 (1H, d, J=7.8 Hz), 7.54 (1H, d, J=7.8 Hz),7.74 (1H, t, J=7.8 Hz).

Example 301

3-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propyl acetate

3-(6-Cyano-2-pyridyl)propyl acetate (1.5 g, 7.3 mmol) and methylthiosalicylate (1.9 g, 11.0 mmol) were dissolved in toluene (5 ml), andtriethylamine (2.1 ml, 15.1 mmol) was added thereto. The reactionmixture was refluxed for 16 hrs and kept at room temperature toprecipitate crystals. The crystals were washed with toluene andrecrystallized from ethanol to give the titled compound (1.4 g, 56%) aswhite crystals.

mp. 141.3-141.6° C.

¹H-NMR (CDCl₃) δ: 2.07 (3H, s), 2.24 (2H, m), 3.01 (2H, t, J=7.2 Hz),4.24 (2H, t, J=7.2 Hz), 7.39 (1H, d, J=7.5 Hz), 7.60-7.69 (3H, m), 7.81(1H, t, J=7.7 Hz), 8.37 (1H, d, J=7.8 Hz), 8.55 (1H, d, J=7.8 Hz).

IR(KBr): 1729, 1657, 1572, 1537, 1240 cm⁻¹.

Elemental Analysis for C₁₈H₁₆N₂O₃S

Calcd. C, 63.51; H, 4.74; N, 8.23.

Found C, 63.26; H, 4.47; N, 8.04.

Reference Example 115

6-(3-Hydroxypropyl)-2-pyridinecarbonitrile

3-(6-Cyano-2-pyridyl)propyl acetate (3.0 g, 14.7 mmol) was dissolved inmethanol (15 ml), and potassium carbonate (0.08 g, 0.58 mmol) was addedthereto. The reaction mixture was stirred at room temperature for 22 hrsand concentrated to give the titled compound (2.2 g, 92%).

¹H-NMR (CDCl₃) δ: 1.94-2.08 (2H, m), 2.98 (2H, t, J=7.5 Hz), 3.71 (2H,t, J=6.2 Hz), 7.41 (1H, d, J=7.9 Hz), 7.55 (1H, d, J=7.0 Hz), 7.75 (1H,t, J=7.8 Hz).

Example 302

2-[6-(3-Hydroxypropyl)-2-pyridyl]-4H-1,3-benzothiazine-4-on

6-(3-Hydroxypropyl)-2-pyridinecarbonitrile (2.2 g, 13.6 mmol) and methylthiosalicylate (3.7 g, 22.0 mmol) were dissolved in toluene (15 ml), andtriethylamine (3.0 ml, 21.7 mmol) was added thereto. The reactionmixture was refluxed for 30 hrs and subjected to a silica gel (170 g)column chromatography. The fractions eluted with ethyl acetate werecollected and concentrated to give the titled compound (0.61 g, 15%) aswhite crystals.

mp. 145.5-146.0° C.

¹H-NMR (CDCl₃) δ: 2.05-2.18 (2H, m), 3.06 (2H, t, J=7.3 Hz), 3.79 (2H,q, J=7.6 Hz), 7.42 (1H, d, J=7.6 Hz), 7.60-7.69 (3H, m), 7.82 (1H, t,J=7.8 Hz), 8.38 (1H, d, J=7.8 Hz), 8.53 (1H, d, J=7.9 Hz).

IR(KBr): 3520, 1643, 1572, 1534, 1306 cm⁻¹.

Elemental Analysis for C₁₆H₁₄N₂O₂S

Calcd. C, 64.41; H, 4.73; N, 9.39.

Found C, 64.28; H, 4.70; N, 9.50.

Reference Example 116

Ethyl 5-(2-pyridyl)-4-pentenoate

2-Pyridinecarbaldehyde (3.0 g, 28.0 mmol) and(4-ethoxy-4-oxobutyl)triphenylphosphonium (16.7 g, 36.5 mmol) weredissolved in 1,4-dioxane (60 ml), and a solution of potassium carbonate(5.8 g, 42.0 mmol) in water (6 ml) was added thereto. The reactionmixture was refluxed for 18 hrs and combined with ethyl acetate andwater. The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated, and the residuewas subjected to a silica gel. (100 g) column chromatography. Thefractions eluted with hexane-ethyl acetate (4:1, v/v) were collected andconcentrated to give Z-form of the titled compound (2.3 g, 40%). And thefractions eluted with hexane-ethyl acetate (2:1, v/v) were collected andconcentrated to give E-form of the titled compound (1.2 g, 21%)

(Z-form)

¹H-NMR (CDCl₃) δ: 1.24 (3H, t, J=7.2 Hz), 2.49 (2H, t, J=7.2 Hz), 2.96(2H, m), 4.12 (2H, q, J=7.2 Hz), 5.86 (1H, dt, J=7.2, 11.8 Hz), 6.46(1H, d, J=11.8 Hz), 7.11 (1H, m), 7.23 (1H, t, J=7.8 Hz), 7.63 (1H, t,J=7.8 Hz), 8.60 (1H, d, J=5.7 Hz).

(E-form)

¹H-NMR (CDCl₃) δ: 1.26 (3H, t, J=7.2 Hz), 2.34-2.63 (4H, m), 4.12 (2H,q, J=7.2 Hz), 6.52 (1H, d, J=15.9 Hz), 6.73 (1H, dt, J=6.6, 15.9 Hz),7.11 (1H, m), 7.24 (1H, t, J=7.8 Hz), 7.60 (1H, t, J=7.8 Hz), 8.53 (1H,d, J=5.7 Hz).

Reference Example 117

Ethyl 5-(2-pyridyl)valerate

Ethyl 5-(2-pyridyl)-4-pentenoate (1.7 g, 8.2 mmol) was dissolved inethanol (20 ml), and 10% palladium-carbon (0.22 g) and a solution ofammonium formate (3.1 g, 49.0 mmol) in water (5 ml) were added thereto.The reaction mixture was refluxed for 2 hrs. Palladium-carbon wasfiltered off, and the reaction mixture was combined with ethyl acetateand water. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated to give thetitled compound (1.6 g, 94%).

¹H-NMR (CDCl₃) δ: 1.24 (3H, t, J=7.2 Hz), 1.66-1.81 (4H, m) 2.31 (2H, t,J=7.5 Hz), 2.81 (2H, t, J=7.2 Hz), 4.12 (2H, q, J=7.2 Hz), 7.08-7.18(2H, m), 7.59 (1H, t, J=7.8 Hz), 8.52 (1H, d, J=6.0 Hz)

Reference Example 118

Ethyl 5-(1-oxide-2-pyridyl)valerate

Ethyl 5-(2-pyridyl)valerate (0.75 g, 3.2 mmol) was dissolved in ethylacetate (5 ml), and 3-chloroperbenzoic acid (0.72 g, 3.3 mmol) was addedthereto. The reaction mixture was stirred at room temperature for 15 hrsand subjected to a silica gel (40 g) column chromatography. Thefractions eluted with ethyl acetate-ethanol (3:1, v/v) were collectedand concentrated to give the titled compound (0.51 g, 64%).

¹H-NMR (CDCl₃) δ: 1.25 (3H, t, J=7.2 Hz), 1.68-1.84 (4H, m), 2.37 (2H,t, J=7.2 Hz), 2.95 (2H, t, J=7.2 Hz), 4.13 (2H, q, J=7.2 Hz), 7.11-7.26(3H, m), 8.25 (1H, d, J=6.0 Hz)

Reference Example 119

Ethyl 5-(6-cyano-2-pyridyl)valerate

Ethyl 5-(1-oxide-2-pyridyl)valerate (0.49 g, 2.2 mmol) was dissolved innitroethane (4 ml), and trimethylsilyl cyanide (0.45 g, 4.5 mmol) andN,N-dimethylcarbamoyl chloride (0.48 g, 4.5 mmol) were added thereto.The reaction mixture was stirred at room temperature for 18 hrs andcombined with ethyl acetate and water. The organic layer was washed withsaturated aqueous sodium hydrogen carbonate solution and saturated brineand dried over anhydrous magnesium sulfate. The solvent was evaporated,and the residue was subjected to a silica gel (20 g) columnchromatography. The fractions eluted with hexane-ethyl acetate (3:1,v/v) were collected and concentrated to give the titled compound (0.35g, 69%).

¹H-NMR (CDCl₃) δ: 1.25 (3H, t, J=7.2 Hz), 1.65-1.82 (4H, m), 2.32 (2H,t, J=7.2 Hz), 2.86 (2H, t, J=7.2 Hz), 4.13 (2H, q, J=7.2 Hz), 7.36 (1H,d, J=7.8 Hz), 7.52 (1H, d, J=7.8 Hz), 7.72 (1H, t, J=7.8 Hz).

Example 303

Ethyl 5-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]valerate

Ethyl 5-(6-cyano-2-pyridyl)valerate (0.34 g, 1.5 mmol) and methylthiosalicylate (0.40 g, 2.4 mmol) were dissolved in toluene (2 ml), andtriethylamine (0.43 ml, 3.1 mmol) was added thereto. The reactionmixture was refluxed for 14 hrs and subjected to a silica gel (25 g)column chromatography. The fractions eluted with hexane-ethyl acetate(3:1, v/v) were collected and concentrated. The residue wasrecrystallized from ethanol-hexane to give the titled compound (0.41 g,76%) as white crystals.

mp. 87.0-88.0° C.

¹H-NMR (CDCl₃) δ: 1.26 (3H, t, J=7.2 Hz), 1.47-1.93 (4H, m), 2.40 (2H,t, J=7.2 Hz), 2.94 (2H, t, J=7.5 Hz), 4.14 (2H, q, J=7.2 Hz), 7.38 (1H,d, J=7.5 Hz), 7.61-7.68 (3H, m), 7.80 (1H, t, J=7.8 Hz), 8.35 (1H, d,J=7.8 Hz), 8.55 (1H, d, J=7.8 Hz).

IR(KBr): 1728, 1658, 1572, 1534, 1238 cm⁻¹.

Elemental Analysis for C₂₀H₂₀N₂O₃S

Calcd. C, 65.20; H, 5.47; N, 7.60.

Found C, 65.10; H, 5.34; N, 7.58.

Example 304

5-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]valeric acid

2-(Trimethylsilyl)ethyl5-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]valerate (0.23 g, 0.52mmol) was dissolved in N,N-dimethylformamide (2 ml), and 1.0 Mtetrabutylammonium fluoride in tetrahydrofuran (1.3 ml, 1.3 mmol) wasadded thereto. The reaction mixture was stirred for 15 minutes andconcentrated under reduced pressure. Trifluoroacetic acid (2.5 ml) wasadded to the residue, and the mixture was stirred at room temperaturefor 1 hr. The reaction mixture was subjected to a silica gel (25 g)column chromatography. The fractions eluted with hexane-ethyl acetate(3:1, v/v) were collected and concentrated. The residue wasrecrystallized from ethanol-acetone to give the titled compound (0.10 g,55%) as white crystals.

mp. 161.9-162.3° C.

¹H-NMR (DMSO-d₆) δ: 1.28-1.98 (4H, m), 2.47 (2H, t, J=7.2 Hz), 2.94 (2H,t, J=7.2 Hz), 7.37 (1H, d, J=7.8 Hz), 7.59-7.70 (3H, m), 7.79 (1H, t,J=7.8 Hz), 8.34 (1H, d, J=7.8 Hz), 8.55 (1H, d, J=6.9 Hz).

IR(KBr): 3200, 1718, 1655, 1570, 1528, 1304 cm⁻¹.

Elemental Analysis for C₁₈H₁₆N₂O₃S

Calcd. C, 63.51; H, 4.74; N, 8.23.

Found C, 63.45; H, 4.85; N, 8.49.

Reference Example 120

2-(Trimethylsilyl)ethyl5-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]valerate

2-(Trimethylsilyl)ethyl 5-(6-cyano-2-pyridyl)valerate (1.0 g, 3.3 mmol)and methyl thiosalicylate (0.85 g, 5.0 mmol) were dissolved in toluene(4 ml), and triethylamine (0.85 ml, 8.4 mmol) was added thereto. Thereaction mixture was refluxed for 10 hrs and subjected to a silica gel(75 g) column chromatography. The fractions eluted with hexane-ethylacetate (4:1, v/v) were collected and concentrated to give the titledcompound (0.38 g, 27%) as white crystals.

¹H-NMR (CDCl₃) δ: 0.03 (9H, s), 0.98 (2H, m), 1.74-1.93 (4H, m) 2.39(2H, t, J=7.2 Hz), 2.94 (2H, t, J=7.2 Hz), 4.16 (2H, m), 7.37 (1H, d,J=7.0 Hz), 7.60-7.69 (3H, m), 7.79 (1H, t, J=7.8 Hz), 8.36 (1H, d, J=7.8Hz), 8.55 (1H, d, J=7.8 Hz).

Reference Example 121

2-(Trimethylsilyl)ethyl 5-(6-cyano-2-pyridyl)valerate

2-(Trimethylsilyl)ethyl 5-(1-oxide-2-pyridyl)valerate (0.94 g, 3.2 mmol)was dissolved in nitroethane (5 ml), and trimethylsilyl cyanide (0.64 g,6.5 mmol) and N,N-dimethylcarbamoyl chloride (0.69 g, 6.4 mmol) wereadded thereto. The reaction mixture was stirred at room temperature for15 hrs and combined with ethyl acetate and saturated aqueous sodiumhydrogen carbonate solution. The organic layer was successively washedwith saturated aqueous sodium hydrogen carbonate solution and saturatedbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated, and the residue was subjected to silica gel (50 g) columnchromatography. The fractions eluted with hexane-ethyl acetate (3:1,v/v) were collected and concentrated to give the titled compound (1.0 g,86%).

¹H-NMR (CDCl₃) δ: 0.04 (9H, s), 0.98 (2H, m), 1.57-1.82 (4H, m), 2.33(2H, t, J=7.2 Hz), 2.85 (2H, t, J=7.2 Hz), 4.16 (2H, m), 7.36 (1H, d,J=7.5 Hz), 7.52 (1H, d, J=7.5 Hz), 7.72 (1H, t, J=7.8 Hz).

Reference Example 122

2-(Trimethylsilyl)ethyl 5-(1-oxide-2-pyridyl)valerate

2-(Trimethylsilyl)ethyl 5-(2-pyridyl)valerate (1.1 g, 4.1 mmol) wasdissolved in ethyl acetate (10 ml), and 3-chloroperbenzoic acid (ca.77%, 1.1 g, 4.8 mmol) was added thereto. The reaction mixture wasstirred at room temperature for 15 hrs and subjected to a silica gel (50g) column chromatography. The fractions eluted with ethylacetate-acetone (2:1, v/v) were collected and concentrated to give thetitled compound (1.0 g, 83%).

¹H-NMR (CDCl₃) δ: 0.04 (9H, s), 0.98 (2H, m), 1.71-1.81 (4H, m), 2.36(2H, t, J=7.2 Hz), 2.95 (2H, t, J=7.2 Hz), 4.17 (2H, m), 7.14-7.26 (3H,m), 8.26 (1H, d, J=6.0 Hz)

Reference Example 123

(2-Trimethylsilyl)ethyl 5-(2-pyridyl)valerate

5-(2-Pyridyl)valeric acid (1.5 g, 8.4 mmol) was dissolved inN,N-dimethylformamide (25 ml), and trimethylsilylethanol (2.0 g, 16.7mmol), WSC (3.2 g, 16.7 mmol) and HOBt (2.3 g, 16.7 mmol) were addedthereto successively. The mixture was stirred at room temperature for 6hrs. The solvent was evaporated, and the residue was combined with ethylacetate and water. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated, andthe residue was subjected to a silica gel (60 g) column chromatography.The fractions eluted with hexane-ethyl acetate (2:1, v/v) were collectedand concentrated to give the titled compound (1.1 g, 49%).

¹H-NMR (CDCl₃) δ: 0.03 (9H, s), 0.97 (2H, m), 1.67-1.81 (4H, m), 2.32(2H, t, J=7.5 Hz), 2.81 (2H, t, J=7.5 Hz), 4.15 (2H, m), 7.07-7.15 (2H,m), 7.58 (1H, t, J=7.8 Hz), 8.52 (1H, d, J=5.4 Hz).

Reference Example 124

5-(2-Pyridyl)valeric acid

Ethyl 5-(2-pyridyl)valerate (3.6 g, 17.2 mmol) was dissolved in ethanol(12 ml), and 2 M aqueous sodium hydroxide solution (12.9 ml, 25.8 mmol)was added thereto. The reaction mixture was stirred at room temperaturefor 1.5 hrs. The solvent was evaporated, and the residue was combinedwith ethanol and filtered to remove the insolubles. The filtrate wasconcentrated to give the titled compound (2.5 g, 82%)

¹H-NMR (DMSO-d₆) δ: 1.17-1.72 (4H, m), 2.23 (2H, t, J=7.2 Hz), 2.72 (2H,t, J=7.2 Hz), 7.16-7.25 (2H, m), 7.68 (1H, t, J=7.8 Hz), 8.46 (1H, d,J=7.8 Hz).

Example 305

2-{6-[2-(1H-1,2,3,4-tetrazol-5-yl)ethyl]-2-pyridyl}-4H-1,3-benzothiazine-4-one

3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propi onitrile (0.25 g,0.85 mmol) and trimethylsilylazide (0.20 g, 1.7 mol) were dissolved intoluene (5 ml), and dibutyltin (IV) oxide (0.02 g, 0.08 mmol) was addedthereto. The reaction mixture was refluxed for 48 hrs and kept at roomtemperature. The precipitated crystals were collected by filtration,washed with toluene and recrystallized from ethanol to give the titledcompound (0.20 g, 68%) as white crystals.

mp. 156.6-157.0° C.

¹H-NMR (DMSO-d₆) δ: 3.37-3.49 (4H, m), 7.67 (1H, d, J=7.6 Hz), 7.75 (1H,t, J=6.6 Hz), 7.84-7.89 (2H, m), 8.03 (1H, t, J=7.7 Hz), 8.20 (1H, d,J=7.6 Hz), 8.36 (1H, d, J=7.8 Hz), 16.10 (1H, bs).

IR(KBr): 3119, 3057, 1658, 1620, 1589, 1523, 1439, 1311 cm⁻¹.

Elemental Analysis for C₁₆H₁₂N₆OS

Calcd. C, 57.13; H, 3.60; N, 24.98.

Found C, 57.31; H, 3.50; N, 24.75.

Example 306

3-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propionitri le

6-(2-Cyanoethyl)-2-pyridinecarbonitrile (0.28 g, 1.8 mmol) and methylthiosalicylate (0.36 g, 2.1 mmol) were dissolved in toluene (2 ml), andtriethylamine (0.37 ml, 2.7 mmol) was added thereto. The reactionmixture was refluxed for 6 hrs and kept at room temperature. Theprecipitated crystals were collected, washed with toluene andrecrystallized from ethanol to give the titled compound (0.28 g, 54%) aswhite crystals.

mp. 156.6-157.0° C.

¹H-NMR (CDCl₃) δ: 3.02 (2H, t, J=7.2 Hz), 3.29 (2H, t, J=7.2 Hz), 7.46(1H, d, J=7.5 Hz), 7.61-7.71 (3H, m), 7.88 (1H, t, J=7.8 Hz), 8.44 (1H,d, J=7.8 Hz), 8.56 (1H, d, J=7.8 Hz).

IR(KBr): 2247, 1659, 1574, 1537, 1439 cm⁻¹.

Elemental Analysis for C₁₆H₁₁N₃OS·0.5H₂O

Calcd. C, 63.56; H, 4.00; N, 13.90.

Found C, 63.81; H, 3.83; N, 13.79.

Reference Example 125

6-(2-Cyanoethyl)-2-pyridinecarbonitrile

3-(1-Oxide-2-pyridyl)propionitrile (0.42 g, 2.8 mmol) was dissolved innitroethane (4 ml), and trimethylsilyl cyanide (0.68 g, 6.9 mmol) andN,N-dimethylcarbamoyl chloride (0.74 g, 6.9 mmol) were added thereto.The reaction mixture was stirred at room temperature for 19 hrs andcombined with ethyl acetate and water. The organic layer wassuccessively washed with saturated aqueous sodium hydrogen carbonatesolution and saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated, and the residue was subjected to a silicagel (20 g) column chromatography. The fractions eluted with hexane-ethylacetate (3:1, v/v) were collected and concentrated to give the titledcompound (0.30 g, 67%)

¹H-NMR (CDCl₃) δ: 2.90 (2H, t, J=7.2 Hz), 3.19 (2H, t, J=7.2 Hz), 7.47(1H, d, J=7.8 Hz), 7.62 (1H, d, J=7.8 Hz), 7.82 (1H, t, J=7.8 Hz).

Reference Example 126

3-(1-Oxide-2-pyridyl)propionitrile

3-(2-Pyridyl)propionitrile (0.41 g, 3.1 mmol) was dissolved in ethylacetate (5 ml), and 3-chloroperbenzoic acid (ca. 77%, 0.82 g, 3.7 mmol)was added thereto. The reaction mixture was stirred at room temperaturefor 21 hrs and subjected to a silica gel (20 g) column chromatography.The fractions eluted with ethyl acetate-acetone (1:1, v/v) werecollected and concentrated to give the titled compound (0.42 g, 91%).

¹H-NMR (CDCl₃) δ: 2.98 (2H, t, J=6.9 Hz), 3.22 (2H, t, J=6.9 Hz),7.23-7.39 (3H, m), 8.27 (1H, d, J=7.8 Hz).

Reference Example 127

3-(2-Pyridyl)propionitrile

(E)-3-(2-Pyridyl)acrylonitrile (0.50 g, 3.8 mmol) was dissolved in2-propanol (10 ml), and sodium borohydride (0.50 g, 13.2 mmol) was addedthereto. The reaction mixture was stirred at 80° C. for 14 hrs andcooled under ice cooling condition, combined with water, concentrated tothe half amount and extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated, and the residue was subjected to a silicagel (25 g) column chromatography. The fractions eluted with hexane-ethylacetate (1:1, v/v) were collected and concentrated to give the titledcompound (0.42 g, 82%).

¹H-NMR (CDCl₃) δ: 2.85 (2H, t, J=7.2 Hz), 3.13 (2H, t, J=7.2 Hz),7.17-7.25 (2H, m), 7.66 (1H, t, J=7.8 Hz), 8.56 (1H, d, J=4.2 Hz).

Reference Example 128

3-(2-Pyridyl)acrylonitrile

Sodium hydride (ca. 60%, 1.0 g, 28.1 mmol) was suspended intetrahydrofuran (12 ml), and a solution of diethyl cyanoethylphosphonate(4.7 g, 26.8 mmol) in tetrahydrofuran (12 ml) was added thereto underice cooling condition. The reaction mixture was stirred for 1 hr. Asolution of 2-pyridinecarbaldehyde (2.7 g, 25.0 mmol) in tetrahydrofuran(10 ml) was added to the mixture, and the mixture was stirred at 0° C.to room temperature for 6 hrs. The reaction mixture was combined withwater under ice cooling condition, concentrated to the half amount andextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over magnesium sulfate. The solvent wasevaporated, and the residue was subjected to a silica gel (100 g) columnchromatography. The fractions eluted with hexane-ethyl acetate (2:1,v/v) were collected and concentrated to give Z-form of the titledcompound (0.50 g, 15%). And simultaneously, the fractions eluted withhexane-ethyl acetate (3:2, v/v) were collected and concentrated to giveE-form of the titled compound.

(Z-form)

¹H-NMR (CDCl₃) δ: 5.67 (1H, d, J=12.1 Hz), 7.28 (1H, d, J=12.1 Hz), 7.33(1H, m), 7.78-7.86 (2H, m), 8.74 (1H, d, J=4.8 Hz).

(E-form)

¹H-NMR (CDCl₃) δ: 6.60 (1H, d, J=16.1 Hz), 7.30-7.35 (2H, m), 7.40 (1H,d, J=16.1 Hz), 7.74 (1H, t, J=7.8 Hz), 8.64 (1H, d, J=5.4 Hz).

Example 307

7-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]heptanoic acid

2-(Trimethylsilyl)ethyl7-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]heptanoate (0.50 g, 1.1mmol) was dissolved in N,N-dimethylformamide (4 ml), and 1.0 Mtetrabutylammonium fluoride solution in tetrahydrofuran (2.6 ml, 2.6mmol) was added thereto. The reaction mixture was stirred for 30 minutesand concentrated under reduced pressure. Trifluoroacetic acid (5 ml) wasadded to the residue, and the mixture was stirred at room temperaturefor 1 hr. The reaction mixture was subjected to a silica gel (40 g)column chromatography. The fractions eluted with hexane-ethyl acetate(1:1, v/v) were collected and concentrated. The residue wasrecrystallized from ethanol-hexane to give the titled compound (0.24 g,61%) as white crystals.

mp. 148.6-150.6° C.

¹H-NMR (DMSO-d₆) δ: 1.43-1.48 (4H, m), 1.69 (2H, t, J=7.2 Hz), 1.86 (2H,t, J=7.2 Hz), 2.38 (2H, t, J=7.5 Hz), 2.91 (2H, t, J=7.5 Hz), 7.36 (1H,d, J=7.5 Hz), 7.59-7.68 (3H, m), 7.79 (1H, t, J=7.8 Hz), 8.34 (1H, d,J=7.8 Hz), 8.55 (1H, d, J=6.9 Hz).

IR(KBr): 3053, 1703, 1659, 1570, 1537, 1298 cm⁻¹.

Elemental Analysis for C₂₀H₂₀N₂O₃S·0.25H₂O

Calcd. C, 64.41; H, 5.54; N, 7.51.

Found C, 64.63; H, 5.32; N, 7.46.

Reference Example 129

2-(Trimethylsilyl)ethyl7-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]heptanoate

2-(Trimethylsilyl)ethyl 7-(6-cyano-2-pyridyl)heptanoate (0.52 g, 1.6mmol) and methyl thiosalicylate (0.43 g, 2.5 mmol) were dissolved intoluene (2 ml), and triethylamine (0.44 ml, 2.3 mmol) was added thereto.The reaction mixture was refluxed for 16 hrs and subjected to a silicagel (35 g) column chromatography. The fractions eluted with hexane-ethylacetate (4:1, v/v) were collected and concentrated to give the titledcompound (0.38 g, 27%) as a yellow oil.

¹H-NMR (CDCl₃) δ: 0.03 (9H, s), 0.98 (2H, m), 1.40-1.45 (4H, m) 1.67(2H, t, J=7.2 Hz), 1.86 (2H, t, J=7.2 Hz), 2.30 (2H, t, J=7.5 Hz), 2.91(2H, t, J=7.5 Hz), 4.16 (2H, m), 7.36 (1H, d, J=7.5 Hz), 7.61-7.68 (3H,m), 7.79 (1H, t, J=7.8 Hz), 8.34 (1H, d, J=7.8 Hz), 8.55 (1H, d, J=7.2Hz).

Reference Example 130

2-(Trimethylsilyl)ethyl 7-(6-Cyano-2-pyridyl)heptanoate

2-(Trimethylsilyl)ethyl 7-(1-oxide-2-pyridyl)heptanoate (0.54 g, 1.7mmol) was dissolved in nitroethane (3 ml), and trimethylsilyl cyanide(0.33 g, 3.3 mmol) and N,N-dimethylcarbamoyl chloride (0.36 g, 3.4 mmol)were added thereto. The reaction mixture was stirred at room temperaturefor 18 hrs and combined with ethyl acetate and saturated aqueous sodiumhydrogen carbonate solution. The organic layer was successively washedwith saturated aqueous sodium hydrogen carbonate solution and saturatedbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated, and the residue was subjected to a silica gel (40 g) columnchromatography. The fractions eluted with hexane-ethylacetate (3:1, v/v)were collected and concentrated to give the titled compound (0.52 g,94%).

¹H-NMR (CDCl₃) δ: 0.04 (9H, s), 0.98 (2H, m), 1.34-1.37 (4H, m), 1.59(2H, t, J=7.2 Hz), 1.74 (2H, t, J=7.2 Hz), 2.27 (2H, t, J=7.2 Hz), 2.82(2H, t, J=7.2 Hz), 4.16 (2H, m), 7.38 (1H, d, J=7.8 Hz), 7.52 (1H, d,J=7.8 Hz), 7.72 (1H, t, J=7.8 Hz).

Reference Example 131

2-(Trimethylsilyl)ethyl 7-(1-oxide-2-pyridyl)heptanoate

2-Trimethylsilylethyl 7-(2-pyridyl)heptanoate (0.77 g, 2.5 mmol) wasdissolved in ethyl acetate (7 ml), and 3-chloroperbenzoic acid (ca. 77%,0.61 g, 2.8 mmol) was added thereto. The reaction mixture was stirred atroom temperature for 14 hrs and subjected to a silica gel (25 g) columnchromatography. The fractions eluted with ethyl acetate-acetone (1:1,v/v) were collected and concentrated to give the titled compound (0.55g, 67%)

¹H-NMR (CDCl₃) δ: 0.04 (9H, s), 0.98 (2H, m), 1.39-1.44 (4H, m)1.62-1.76 (4H, m), 2.28 (2H, t, J=7.5 Hz), 2.92 (2H, t, J=7.5 Hz), 4.16(2H, m), 7.12-7.22 (3H, m), 8.26 (1H, t, J=6.0 Hz).

Reference Example 132

(2-Trimethylsilyl)ethyl 7-(2-pyridyl)heptanoate

7-(2-pyridyl)heptanoic acid (0.89 g, 4.3 mmol) was dissolved inN,N-dimethylformamide (20 ml), and trimethylsilylethanol (1.5 g, 12.9mmol), WSC (2.5 g, 12.9 mmol) and HOBt (1.7 g, 12.9 mmol) weresuccessively added thereto. The reaction mixture was stirred at roomtemperature for 13 hrs. The solvent was evaporated, and the residue wascombined with ethyl acetate and water. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated, and the residue was subjected to a silica gel (40 g)column chromatography. The fractions eluted with hexane-ethyl acetate(3:1, v/v) were collected and concentrated to give the titled compound(0.78 g, 59%).

¹H-NMR (CDCl₃) δ: 0.04 (9H, s), 0.97 (2H, m), 1.34-1.39 (4H, m),1.6-1.75 (4H, m), 2.26 (2H, t, J=7.5 Hz), 2.78 (2H, t, J=7.5 Hz), 4.16(2H, m), 7.07-7.14 (2H, m), 7.58 (1H, t, J=7.7 Hz), 8.51 (1H, d, J=5.7Hz).

Reference Example 133

7-(2-Pyridyl)heptanoic acid

7-(2-Pyridyl)-6-heptenoic acid (0.97 g, 4.7 mmol) was dissolved inethanol (15 ml), and 10% palladium-carbon (0.16 g) and a solution ofammonium formate (1.7 g, 27.0 mmol) in water (2 ml) were added thereto.The reaction mixture was refluxed for 2 hrs. Palladium-carbon wasfiltered off. The reaction mixture was combined with water, concentratedunder reduced pressure to the half amount and extracted with ethylacetate. The organic layer was washed with saturated brine and driedover magnesium sulfate. The solvent was concentrated under reducedpressure to give the titled compound (0.89 g, 91%).

¹H-NMR (DMSO-d₆) δ: 1.29 (4H, m), 1.45-1.50 (2H, m), 1.60-1.65 (2H, m),2.18 (2H, t, J=7.5 Hz), 2.70 (2H, t, J=7.5 Hz), 7.15-7.28 (2H, m), 7.67(1H, t, J=7.6 Hz), 8.46 (1H, d, J=4.6 Hz).

Reference Example 134

7-(2-Pyridyl)-6-heptenoic acid

(5-Carboxypentyl)triphenyl phosphonium (13.7 g, 30.0 mmol) was suspendedin tetrahydrofuran (50 ml), and potassium tert-butoxide (6.3 g, 56.0mmol) was added thereto under ice cooling condition. The mixture wasstirred for 1 hr. Successively, a solution of 2-pyridinecarbaldehyde(2.0 g, 18.7 mmol) in tetrahydrofuran (10 ml) was added to the mixture,and the mixture was stirred at 0° C. for 3 hrs. The reaction mixture wascombined with 2 N aqueous sodium hydroxide solution (50 ml), washed withdiethyl ether, neutralized with 6 N HCl and extracted with ethylacetate. The organic layer was washed with saturated brine and driedover magnesium sulfate. The solvent was evaporated, and the residue wassubjected to a silica gel (100 g) column chromatography. The fractionseluted with hexane-ethyl acetate (1:1, v/v) were collected andconcentrated to give Z-form of the titled compound (2.0 g, 52%). And thefractions eluted with hexane-ethyl acetate (1:2, v/v) were collected andconcentrated to give a mixture of E-form and Z-form of the titledcompound (0.97 g, 25%)

(Z-form)

¹H-NMR (CDCl₃) δ: 1.40-1.75 (4H, m), 2.35 (2H, m), 2.56 (2H, t, J=7.2Hz), 5.88 (1H, dt, J=7.5 & 11.8 Hz), 6.49 (1H, d, J=11.8 Hz), 7.14 (1H,m), 7.23 (1H, d, J=7.8 Hz), 7.66 (1H, t, J=7.8 Hz), 8.60 (1H, d, J=5.7Hz)

(E-form)

¹H-NMR (CDCl₃) δ: 1.50-1.80 (4H, m), 2.20-2.42 (4H, m), 6.52 (1H, d,J=15.8 Hz), 6.73 (1H, dt, J=6.7 & 15.9 Hz), 7.12 (1H, m), 7.27 (1H, t,J=7.8 Hz), 7.63 (1H, t, J=7.8 Hz), 8.55 (1H, d, J=7.8 Hz).

Example 308

3-[2-(4-Oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propionic acid

tert-Butyl 3-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propionate(0.45 g, 1.2 mmol) was dissolved in trifluoroacetic acid (3.0 ml), andthe mixture was stirred at room temperature for 2.5 hrs. Isopropyl etherwas added to the reaction mixture to precipitate crystals, which werecollected by filtration and washed with ethanol-hexane to give thetitled compound (0.32 g, 84%) as white crystals.

mp. 215.3-215.9° C.

¹H-NMR (DMSO-d₆) δ: 2.69 (2H, t, J=7.4 Hz), 3.01 (2H, t, J=7.4 Hz), 7.65(1H, t, J=7.4 Hz), 7.75 (1H, t, J=7.6 Hz), 7.84 (1H, m), 7.90 (1H, m),8.25 (1H, s), 8.36 (1H, d, J=7.9 Hz), 8.69 (1H, d, J=4.9 Hz).

IR(KBr): 3086, 3055, 1714, 1653, 1591, 1568, 1522, 1444 cm⁻¹.

Elemental Analysis for C₁₆H₁₂N₂O₃S

Calcd. C, 61.53; H, 3.87; N, 8.97.

Found C, 61.42; H, 3.96; N, 8.92.

Example 309

tert-butyl 3-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propionate

tert-Butyl 3-(2-cyano-4-pyridyl)propionate (0.51 g, 2.2 mmol) and methylthiosalicylate (0.55 g, 3.3 mmol) were dissolved in toluene (2 ml), andtriethylamine (0.47 ml, 3.4 mmol) was added thereto. The mixture wasrefluxed for 8 hrs and subjected to a silica gel (30 g) columnchromatography. The fractions eluted with hexane-ethyl acetate (3:1,v/v) were collected and concentrated to give the titled compound (0.56g, 69%) as white crystals.

mp. 135.8-136.7° C.

¹H-NMR (CDCl₃) δ: 1.43 (9H, s), 2.65 (2H, t, J=7.6 Hz), 3.03 (2H, t,J=7.6 Hz), 7.41 (1H, t, J=4.9 Hz), 7.60-7.70 (3H, m), 8.43 (1H, s), 8.56(1H, d, J=8.1 Hz), 8.63 (1H, d, J=4.7 Hz).

IR(KBr): 1726, 1664, 1572, 1537, 1365 cm⁻¹.

Elemental Analysis for C₂₀H₂₀N₂O₃S

Calcd. C, 65.20; H, 5.47; N, 7.60.

Found C, 65.16; H, 5.52; N, 7.51.

Reference Example 135

tert-Butyl 3-(2-Cyano-4-pyridyl)propionate

tert-Butyl 3-(4-pyridyl)propionate (0.58 g, 2.8 mmol) was dissolved inethyl acetate (4 ml), and 3-chloroperbenzoic acid (ca. 77%, 0.65 g, 2.9mmol) was added thereto. The reaction mixture was stirred at roomtemperature for 18 hrs and subjected to a silica gel (35 g) columnchromatography. The fractions eluted with ethyl acetate-ethanol (3:1,v/v) were collected and concentrated. The residue was dissolved innitroethane (4 ml), and trimethylsilyl cyanide (0.50 g, 5.1 mmol) andN,N-dimethylcarbamoyl chloride (0.54 g, 5.1 mmol) were added thereto.The reaction mixture was stirred at room temperature for 16 hrs andcombined with ethyl acetate and water. The organic layer wassuccessively washed with saturated aqueous sodium hydrogen carbonatesolution and saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated, and the residue was subjected to a silicagel (30 g) column chromatography. The fractions eluted with hexane-ethylacetate (4:1, v/v) were collected and concentrated to give the titledcompound (0.52 g, 79%).

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 2.59 (2H, t, J=7.4 Hz), 2.97 (2H, t,J=7.4 Hz), 7.37 (1H, d, J=7.8 Hz), 7.56 (1H, s), 8.61 (1H, d, J=7.8 Hz).

Reference Example 136

tert-Butyl 3-(4-pyridyl)propionate

tert-Butyl (E)-3-(4-Pyridyl)acrylate (0.88 g, 4.3 mmol) was dissolved inethanol (10 ml), and 10% palladium-carbon (0.17 g) and a solution ofammonium formate (1.4 g, 21.4 mmol) in water (2.5 ml) were addedthereto. The reaction mixture was refluxed for 3 hrs. Palladium-carbonwas filtered off. The reaction mixture was combined with water,concentrated under reduced pressure to the half amount and extractedwith ethyl acetate. The organic layer was washed with saturated brineand dried over magnesium sulfate. The solvent was evaporated, and theresidue was subjected to a silica gel (20 g) column chromatography. Thefractions eluted with hexane-ethyl acetate (3:1, v/v) were collected andconcentrated to give the titled compound (0.58 g, 65%).

¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 2.56 (2H, t, J=7.5 Hz), 2.91 (2H, t,J=7.5 Hz), 7.13 (2H, d, J=6.0 Hz), 8.50 (2H, d, J=6.0 Hz).

Reference Example 137

tert-Butyl (E)-3-(4-pyridyl)acrylate

Sodium hydride (0.43 g, 10.8 mmol) was suspended in tetrahydrofuran (5ml), and a solution of tert-butyl diethylphosphonoacetate (2.5 g, 9.8mmol) in tetrahydrofuran (2 ml) was added thereto under ice coolingcondition. The mixture was stirred for 0.5 hr. Successively, a solutionof 4-pyridinecalbaldehyde (1.0 g, 9.3 mmol) in tetrahydrofuran (3 ml)was added to the mixture, and the mixture was stirred at 0° C. for 2hrs. The reaction mixture was combined with water, concentrated underreduced pressure to the half amount and extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overmagnesium sulfate. The solvent was evaporated to give the titledcompound (1.8 g, 92%).

¹H-NMR (CDCl₃) δ: 1.54 (9H, s), 6.52 (1H, d, J=16.0 Hz), 7.35 (2H, d,J=4.5 Hz), 7.49 (1H, d, J=16.0 Hz), 8.64 (2H, d, J=4.5 Hz).

Example 310

(E)-3-[2-(4-Oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]acrylic acid

tert-Butyl (E)-3-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]acrylat e(0.14 g, 0.44 mmol) was dissolved in trifluoroacetic acid (2.0 ml), andthe mixture was stirred at room temperature for 2.5 hrs. Isopropyl etherwas added to the reaction mixture to precipitate crystals, which werecollected by filtration and recrystallized from tetrahydrofuran-ethanolto give the titled compound (0.088 g, 64%) as white crystals.

mp. 284.3-285.0° C.

¹H-NMR (DMSO-d₆) δ: 6.91 (1H, d, J=16.1 Hz), 7.73 (1H, d, J=16.1 Hz),7.73 (1H, m), 7.83 (1H, t, J=7.2 Hz), 7.92 (1H, m), 8.05 (1H, d, J=7.9Hz), 8.37 (1H, d, J=7.9 Hz), 8.50 (1H, s), 8.83 (1H, d, J=5.0 Hz).

IR(KBr): 3113, 3061, 1711, 1626, 1572, 1532, 1315 cm⁻¹.

Elemental Analysis for C₁₆H₁₀N₂O₃S

Calcd. C, 61.93; H, 3.25; N, 9.03.

Found C, 61.68; H, 3.23; N, 8.99.

Example 311

tert-Butyl (E)-3-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]acrylat e

tert-Butyl (E)-3-(2-cyano-4-pyridyl)acrylate (0.84 g, 3.2 mmol) andmethyl thiosalicylate (0.74 g, 4.4 mmol) were dissolved in toluene (3ml), and triethylamine (0.77 ml, 5.5 mmol) was added thereto. Thereaction mixture was refluxed for 7 hrs and subjected to a silica gel(50 g) column chromatography. The fractions eluted with hexane-ethylacetate (3:1, v/v) were collected and concentrated. The residue wasrecrystallized from ethyl acetate-isopropyl ether to give the titledcompound (0.16 g, 17%) as white crystals.

mp. 196.0-196.7° C.

¹H-NMR (CDCl₃) δ: 1.56 (9H, s), 6.72 (1H, d, J=16.1 Hz), 7.55-7.71 (5H,m), 8.56 (1H, d, J=8.0 Hz), 8.64 (1H, s), 8.74 (1H, d, J=4.9 Hz).

IR(KBr): 1711, 1661, 1572, 1537, 1367, 1325 cm⁻¹.

Elemental Analysis for C₂₀H₁₈N₂O₃S

Calcd. C, 65.55; H, 4.95; N, 7.64.

Found C, 65.48; H, 4.91; N, 7.58.

Reference Example 138

tert-Butyl (E)-3-(2-cyano-4-pyridyl)acrylate

tert-Butyl (E)-3-(4-pyridyl)acrylate (0.88 g, 4.3 mmol) was dissolved inethyl acetate (4 ml), and 3-chloroperbenzoic acid (ca. 77%, 0.95 g, 4.3mmol) was added thereto. The reaction mixture was stirred at roomtemperature for 45 hrs and subjected to a silica gel (40 g) columnchromatography. The fractions eluted with ethyl acetate-ethanol (4:1)were collected and concentrated. The residue was dissolved innitroethane (5 ml), and trimethylsilyl cyanide (0.63 g, 6.3 mmol) andN,N-dimethylcarbamoyl chloride (0.68 g, 6.3 mmol) were added thereto.The reaction mixture was stirred at room temperature for 20 hrs andcombined with ethyl acetate and water. The organic layer wassuccessively washed with saturated aqueous sodium hydrogen carbonatesolution and saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated, and the residue was subjected to silica gel(30 g) column chromatography. The fractions eluted with hexane-ethylacetate (5:1, v/v) were collected and concentrated to give the titledcompound (0.73 g, 99%).

¹H-NMR (CDCl₃) δ: 1.54 (9H, s), 6.58 (1H, d, J=16.0 Hz), 7.47 (1H, d,J=16.0 Hz), 7.55 (1H, d, J=5.1 Hz), 7.75 (1H, s), 8.74 (1H, d, J=5.1 Hz)

Example 312({3-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoyl}amino)aceticacid

tert-Butyl({3-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoyl}amino)acetate(0.27 g, 0.63 mmol) was dissolved in trifluoroacetic acid (1.5 ml), andthe mixture was stirred at room temperature for 2.5 hrs. Isopropyl etherwas added to the reaction mixture to precipitate crystals, which werecollected by filtration and recrystallized from tetrahydrofuran-ethanolto give the titled compound (0.12 g, 49%) as white crystals.

mp. 219.2-219.8° C.

¹H-NMR (DMSO-d₆) δ: 2.71 (2H, t, J=7.3 Hz), 3.14 (2H, t, J=7.3 Hz), 3.78(2H, d, J=5.9 Hz), 7.64 (1H, t, J=7.3 Hz), 7.73 (1H, t, J=7.3 Hz), 7.83(1H, t, J=7.3 Hz), 7.93-8.03 (2H, m), 8.19 (1H, d, J=7.7 Hz), 8.29 (1H,m), 8.36 (1H, d, J=7.9 Hz), 12.47 (1H, bs).

IR(KBr): 3055, 1759, 1651, 1589, 1514, 1439 cm⁻¹.

Elemental Analysis for C₁₁H₁₅N₃O₄S

Calcd. C, 58.53; H, 4.09; N, 11.38.

Found C, 58.40; H, 4.22; N, 11.15.

Reference Example 139

tert-Butyl({3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoyl}amino)acetate

3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propi onic acid (0.20 g,0.64 mmol) as dissolved in N,N-dimethylformamide (3 ml), and glycinetert-butyl ester (0.11 g, 0.67 mmol), WSC (0.25 g, 1.3 mmol) and HOBt(0.18 g, 1.3 mmol) were added successively thereto. The reaction mixturewas stirred at room temperature for 17 hrs, concentrated under reducedpressure and combined with ethyl acetate and water. The organic layerwas washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated, and the residue was subjected to asilica gel (15 g) column chromatography. The fractions eluted withhexane-ethylacetate (1:1, v/v) were collected and concentrated to givethe titled compound (0.27 g, 99%) as white crystals.

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 2.90 (2H, t, J=7.2 Hz), 3.30 (2H, t,J=7.2 Hz), 3.96 (2H, d, J=4.9 Hz), 6.31 (1H, bs), 7.43 (1H, d, J=7.6Hz), 7.62-7.69 (3H, m), 7.80 (1H, t, J=7.8 Hz), 8.34 (1H, d, J=7.6 Hz),8.56 (1H, d, J=7.5 Hz).

Example 313

1-{3-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoy l}proline

tert-Butyl 1-{3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoyl}-2-pyrrolidinecarboxylate (0.25 g, 0.68 mmol) was dissolved intrifluoroacetic acid (2 ml), and the mixture was stirred at roomtemperature for 2.5 hrs. Isopropyl ether was added to the reactionmixture to precipitate crystals, which were collected by filtration andrecrystallized from ethanol-hexane to give the titled compound (0.13 g,45%) as white crystals.

mp. 210.5-211.0° C.

¹H-NMR (DMSO-d₆) δ: 1.70-2.20 (4H, m), 2.80-2.90 (2H, m), 3.10-3.16 (2H,m), 3.30-3.70 (2H, m), 4.24 & 4.61 (1H, m), 7.66-7.75 (2H, m), 7.81-7.95(2H, m), 8.00 (1H, t, J=7.8 Hz), 8.18 (1H, d, J=7.7 Hz), 8.36 (1H, d,J=7.8 Hz), 12.45 (1H, bs).

IR(KBr): 3248, 1736, 1659, 1572, 1537, 1439 cm⁻¹.

Elemental Analysis for C₂₁H₁₉N₃O₄S·0.25H₂O

Calcd. C, 60.93; H, 4.75; N, 10.15.

Found C, 60.92; H, 4.71; N, 10.22.

Reference Example 140

tert-Butyl 1-{3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoyl}-2-pyrrolidinecarboxylate

3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propi onic acid (0.25 g,0.80 mmol) was dissolved in N,N-dimethylformamide (3 ml), and prolinetert-butyl ester (0.15 g, 0.88 mmol), WSC (0.31 g, 1.6 mmol) and HOBt(0.22 g, 1.6 mmol) were successively added thereto. The reaction mixturewas stirred for 18 hrs, concentrated under reduced pressure and combinedwith ethyl acetate and water. The organic layer was washed withsaturated brine and dried over magnesium sulfate. The solvent wasevaporated, and the residue was recrystallized from isopropyl ether togive the titled compound (0.29 g, 78%) as white crystals.

¹H-NMR (CDCl₃) δ: 1.45 (9H, d, J=3.3 Hz), 1.92-2.16 (4H, m) 2.90-2.97(2H, m), 3.24-3.32 (2H, m), 3.55-3.75 (2H, m), 4.42 (1H, m), 7.46 (1H,d, J=7.6 Hz), 7.60-7.70 (3H, m), 7.78 (1H, t, J=7.7 Hz), 8.32 (1H, d,J=7.8 Hz), 8.57 (1H, d, J=8.0 Hz).

Example 314

(Methyl{3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoyl}amino)acetic acid

tert-Butyl (methyl{3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoyl}amino)acetate (0.32 g, 0.73 mmol) was dissolved intrifluoroacetic acid (1.0 ml), and the mixture was stirred at roomtemperature for 2.5 hrs. Isopropyl ether was added to the reactionmixture to precipitate crystals, which were collected by filtration andrecrystallized from ethanol-hexane to give the titled compound (0.25 g,83%) as white crystals.

mp. 194.5-194.8° C.

¹H-NMR (DMSO-d₆) δ: 2.78-2.95 (4H, m), 3.33 (2H, s), 4.02 & 4.24 (3H,s), 7.65-7.83 (3H, m), 7.90-8.02 (2H, m), 8.17 (1H, d, J=7.7 Hz), 8.35(1H, d, J=7.9 Hz), 12.69 (1H, bs).

IR(KBr): 3055, 1759, 1651, 1603, 1589, 1514, 1439 cm⁻¹.

Elemental Analysis for C₁₉H₁₇N₃O₄S

Calcd. C, 59.52; H, 4.47; N, 10.96.

Found C, 59.53; H, 4.53; N, 11.12.

Reference Example 141

tert-Butyl (methyl(3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoyl]amino)acetate

3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propi onic acid (0.35 g,1.1 mmol) was dissolved in N,N-dimethylformamide (4 ml), andN-methylglycine tert-butyl ester (0.24 g, 1.3 mmol), WSC (0.43 g, 2.2mmol) and HOBt (0.31 g, 2.3 mmol) were successively added thereto. Thereaction mixture was stirred for 20 hrs, concentrated under reducedpressure and combined with ethyl acetate and water. The organic layerwas washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated, and the residue was recrystallizedfrom ethanol-hexane to give the titled compound (0.33 g, 67%) as whitecrystals.

¹H-NMR (CDCl₃) δ: 1.45 & 1.47 (9H, s), 2.85-3.05 (2H, m), 3.01 & 3.16(3H, s), 3.28 (2H, m), 4.04 & 4.05 (2H, s), 7.47 (1H, d, J=7.5 Hz),7.60-7.69 (3H, s), 7.79 (1H, t, J=7.7 Hz), 8.34 (1H, d, J=7.8 Hz), 8.56(1H, d, J=7.9 Hz).

Example 315

Ethyl 2-methyl-3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propionate

Ethyl 3-(6-cyano-2-pyridyl)-2-methylpropionate (0.79 g, 3.6 mmol) andmethyl thiosalicylate (1.2 g, 7.3 mmol) were dissolved in toluene (3ml), and triethylamine (0.76 ml, 5.4 mmol) was added thereto. Thereaction mixture was refluxed for 21 hrs and subjected to a silica gel(70 g) column chromatography. The fractions eluted with hexane-ethylacetate (2:1, v/v) were collected and concentrated to give the titledcompound (0.89 g, 70%) as white crystals.

mp. 120.2-120.7° C.

¹H-NMR (CDCl₃) δ: 1.21 (3H, t, J=7.1 Hz), 1.31 (3H, d, J=6.9 Hz), 3.00(1H, dd, J=14.0 & 5.9 Hz), 3.21-3.37 (2H, m), 4.08-4.20 (2H, m), 7.41(1H, d, J=7.5 Hz), 7.60-7.70 (3H, m), 7.80 (1H, t, J=7.8 Hz), 8.37 (1H,d, J=7.8 Hz), 8.57 (1H, d, J=8.0 Hz).

IR(KBr): 1728, 1651, 1591, 1574, 1537, 1452 cm⁻¹.

Elemental Analysis for C₁₉H₁₈N₂O₃S

Calcd. C, 64.39; H, 5.12; N, 7.90.

Found C, 64.36; H, 5.10; N, 7.88.

Reference Example 142

Ethyl 3-(6-cyano-2-pyridyl)-2-methylpropionate

Ethyl 2-methyl-3-(2-pyridyl)propionate (1.0 g, 5.2 mmol) was dissolvedin ethyl acetate (4 ml), and 3-chloroperbenzoic acid (ca. 77%, 1.2 g,5.2 mmol) was added thereto. The reaction mixture was stirred at roomtemperature for 14 hrs and subjected to a silica gel (50 g) columnchromatography. The fractions eluted with ethyl acetate-ethanol (4:1,v/v) were collected and concentrated. The residue was dissolved inacetonitrile (10 ml), and trimethylsilyl cyanide (0.95 g, 9.6 mmol) andN,N-dimethylcarbamoyl chloride (0.77 g, 7.2 mmol) were added thereto.The reaction mixture was stirred at room temperature for 16 hrs andcombined with ethyl acetate and water. The organic layer was washed withsaturated aqueous sodium hydrogen carbonate solution and saturated brineand dried over anhydrous magnesium sulfate. The solvent was evaporated,and the residue was subjected to a silica gel (50 g) columnchromatography. The fractions eluted with hexane-ethyl acetate (4:1,v/v) were collected and concentrated to give the titled compound (0.80g, 76%).

¹H-NMR (CDCl₃) δ: 1.22 (3H, t, J=7.3 Hz), 1.23 (3H, d, J=7.1 Hz), 2.90(1H, dd, J=13.7 & 6.0 Hz), 3.03-3.27 (2H, m), 4.11 (2H, q, J=7.1 Hz),7.38 (1H, d, J=7.8 Hz), 7.53 (1H, d, J=7.8 Hz), 7.72 (1H, t, J=7.8 Hz).

Reference Example 143

Ethyl 2-methyl-3-(2-pyridyl)propionate

Ethyl 2-methyl-3-(2-pyridyl)acrylate (7.8 g, 41.0 mmol) was dissolved inethanol (80 ml), and 10% palladium-carbon (1.0 g) and a solution ofammonium formate (11.2 g, 178 mmol) in water (20 ml) was added thereto.The mixture was refluxed for 2 hrs. Palladium-carbon was filtered off.The reaction mixture was combined with water, concentrated under reducedpressure to the half amount and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated to give the titledcompound (7.2 g, 91%).

¹H-NMR (CDCl₃) δ: 1.18 (3H, d, J=7.1 Hz), 1.19 (3H, t, J=7.1 Hz), 2.83(1H, dd, J=13.5 & 7.0 Hz), 3.03 (1H, m), 3.19 (1H, dd, J=13.5 & 7.4 Hz),4.10 (2H, q, J=7.1 Hz), 7.09-7.15 (2H, m), 7.58 (1H, d, J=7.1 Hz), 8.53(1H, d, J=4.7 Hz).

Reference Example 144

Ethyl 2-methyl-3-(2-pyridyl)acrylate

Sodium hydride (ca. 60%, 2.0 g, 50.0 mmol) was suspended intetrahydrofuran (20 ml), and a solution of ethyl2-(diethylphosphono)propionate (11.7 g, 49.1 mmol) in tetrahydrofuran (8ml) was added thereto under ice cooling condition. The mixture wasstirred for 0.5 hr. Successively, a solution of 2-pyridinecarbaldehyde(5.0 g, 46.7 mmol) in tetrahydrofuran (8 ml) was added to the mixture.The mixture was stirred at 0° C. for 14 hrs, combined with water,concentrated under reduced pressure to the half amount and extractedwith ethyl acetate. The organic layer was washed with saturated brineand dried over anhydrous magnesium sulfate. The solvent was evaporated,and the residue was subjected to a silica gel (80 g) columnchromatography. The fractions eluted with hexane-ethyl acetate (3:1,v/v) were collected and concentrated to give the titled compound (7.8 g,87%).

¹H-NMR (CDCl₃) δ: 1.35 (3H, t, J=7.1 Hz), 2.33 (3H, d, J=1.4 Hz), 4.29(2H, q, J=7.1 Hz), 7.20 (1H, m), 7.38 (1H, d, J=7.8 Hz), 7.64 (1H, d,J=1.4 Hz), 7.71 (1H, t, J=7.8 Hz), 8.68 (1H, d, J=4.8 Hz)

Example 316

2-{4-[2-(1H-1,2,3,4-Tetrazol-5-yl)ethyl]-2-pyridyl}-4H-1,3-benzothiazine-4-one

3-[2-(4-Oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propi onitrile (0.25 g,0.85 mmol) and trimethylsilyl azide (0.20 g, 1.7 mmol) were dissolved intoluene (5 ml), and dibutyltin (IV) oxide (0.02 g, 0.08 mmol) was addedthereto. The reaction mixture was refluxed for 48 hrs and kept at roomtemperature. The precipitated crystals were collected by filtration andwashed with toluene. The obtained crystals were recrystallized fromethanol to give the titled compound (0.13 g, 44%) as white crystals.

mp. 250.0° C. (decomp.)

¹H-NMR (DMSO-d₆) δ: 3.25-3.34 (4H, m), 7.63 (1H, d, J=3.7 Hz), 7.73 (1H,t, J=7.0 Hz), 7.81-7.93 (2H, m), 8.29 (1H, s), 8.36 (1H, d, J=7.0 Hz),8.69 (1H, d, J=5.2 Hz), 16.10 (1H, bs).

IR(KBr): 3140, 3063, 1657, 1612, 1601, 1587, 1529, 1518, 1441, 1319cm⁻¹.

Elemental Analysis for C₁₆H₁₂N₆OS

Calcd. C, 57.13; H, 3.60; N, 24.98.

Found C, 57.31; H, 3.50; N, 24.75.

Example 317

3-[2-(4-Oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propionitri le

4-(2-Cyanoethyl)-2-pyridinecarbonitrile (0.70 g, 4.5 mmol) and methylthiosalicylate (1.1 g, 6.2 mmol) were dissolved in toluene (3.5 ml), andtriethylamine (1.2 ml, 8.9 mmol) was added thereto. The reaction mixturewas refluxed for 8 hrs and kept at room temperature. The precipitatedcrystals were collected by filtration and washed with toluene. Theobtained crystals were recrystallized from tetrahydrofuran-ethanol togive the titled compound (0.66 g, 51%) as white crystals

mp. 178.3-179.0° C.

¹H-NMR (CDCl₃) δ: 2.77 (2H, t, J=7.2 Hz), 3.10 (2H, t, J=7.2 Hz), 7.48(1H, d, J=5.0 Hz), 7.60-7.72 (3H, m), 8.44 (1H, s), 8.58 (1H, d, J=8.0Hz), 8.72 (1H, d, J=4.9 Hz)

IR(KBr): 2247, 1659, 1599, 1570, 1537, 1439, 1298 cm⁻¹.

Elemental Analysis for C₁₆H₁₁N₃OS·0.5H₂O

Calcd. C, 63.56; H, 4.00; N, 13.90.

Found C, 63.81; H, 3.83; N, 13.79.

Reference Example 145

4-(2-Cyanoethyl)-2-pyridinecarbonitrile

3-(1-Oxide-2-pyridyl)propionitrile (0.89 g, 5.9 mmol) was dissolved inacetonitrile (10 ml), and trimethylsilyl cyanide (1.2 g, 12.1 mmol) andN,N-dimethylcarbamoyl chloride (1.1 g, 10.3 mmol) were added thereto.The reaction mixture was stirred at room temperature for 16 hrs andcombined with ethyl acetate and water. The organic layer wassuccessively washed with saturated aqueous sodium hydrogen carbonatesolution and saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated, and the residue was subjected to a silicagel (20 g) column chromatography. The fractions eluted with hexane-ethylacetate (2:1, v/v) were collected and concentrated to give the titledcompound (0.71 g, 76%).

¹H-NMR (CDCl₃) δ: 2.72 (2H, t, J=7.1 Hz), 3.05 (2H, t, J=7.1 Hz), 7.45(1H, d, J=5.0 Hz), 7.60 (1H, s), 8.71 (1H, d, J=5.0 Hz).

Reference Example 146

3-(1-Oxide-2-pyridyl)propionitrile

3-(4-Pyridyl)propionitrile (0.88 g, 6.7 mmol) was dissolved in ethylacetate (8 ml), and 3-chloroperbenzoic acid (ca. 77%, 1.5 g, 6.7 mmol)was added thereto. The reaction mixture was stirred at room temperaturefor 48 hrs and subjected to a silica gel (25 g) column chromatography.The fractions eluted with ethyl acetate-ethanol (3:1, v/v) werecollected and concentrated to give the titled compound (0.89 g, 91%).

¹H-NMR (CDCl₃) δ: 2.67 (2H, t, J=7.1 Hz), 2.97 (2H, t, J=7.1 Hz), 7.18(2H, d, J=6.8 Hz), 8.19 (2H, d, J=6.8 Hz).

Reference Example 147

3-(4-Pyridyl)propionitrile

3-(4-Pyridyl)acrylonitrile (1.3 g, 10.0 mmol) was dissolved in ethanol(10 ml), and 10% palladium-carbon (0.13 g) and a solution of ammoniumformate (2.5 g, 40.0 mmol) in water (3 ml) were added thereto. Thereaction mixture was refluxed for 2.5 hrs. Palladium-carbon was filteredoff, and the reaction mixture was combined with ethyl acetate and water.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The reaction mixture was subjected to asilica gel (25 g) column chromatography. The fractions eluted withhexane-ethyl acetate (1:1, v/v) were collected and concentrated to givethe titled compound (0.88 g, 67%)

¹H-NMR (CDCl₃) δ: 2.67 (2H, t, J=7.3 Hz), 2.97 (2H, t, J=7.3 Hz), 7.18(2H, d, J=6.0 Hz), 8.59 (2H, d, J=6.0 Hz).

Reference Example 148

3-(4-Pyridyl)acrylonitrile

Sodium hydride (ca. 60%, 1.0 g, 28.1 mmol) was dissolved intetrahydrofuran (10 ml), and a solution of diethylcyanomethylphosphonate (4.7 g, 26.8 mmol) in tetrahydrofuran (5 ml) wasadded under ice cooling condition. The mixture was stirred for 1 hr.Successively, a solution of 2-pyridinecarbaldehyde (2.7 g, 25.0 mmol) intetrahydrofuran (5 ml) was added to the mixture, and the mixture wasstirred at 0° C. to room temperature for 3 hrs. The reaction mixture wascombined with water under ice cooling condition, concentrated underreduced pressure to the half amount and extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overmagnesium sulfate. The solvent was evaporated, and the residue wassubjected to a silica gel (100 g) column chromatography. The fractionseluted with hexane-ethyl acetate (2:1, v/v) were collected andconcentrated to give the titled compound (a mixture of E-form andZ-form, 2.5 g, 77%).

¹H-NMR (CDCl₃) δ: 5.70 (0.18H, d, J=12.1 Hz), 6.10 (0.82H, d, J=16.7Hz), 7.12 (0.18H, d, J=12.1 Hz), 7.29 (0.82H, d, J=16.7 Hz), 7.30-7.39(1.6H, m), 7.63 (0.4H, d, J=6.2 Hz), 8.70 (1.6H, d, J=6.2 Hz), 8.75(0.4H, d, J=6.2 Hz).

Example 318

Ethyl 2-methyl-3-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propionate

Ethyl 3-(2-cyano-4-pyridyl)-2-methylpropionate (0.50 g, 2.3 mmol) andmethyl thiosalicylate (0.96 g, 5.7 mmol) were dissolved in toluene (2ml), and triethylamine (11.0 ml, 5.7 mmol) was added thereto. Thereaction mixture was refluxed for 8 hrs and combined with isopropylether to precipitate crystals, which were collected by filtration andrecrystallized from ethyl acetate to give the titled compound (0.43 g,53%) as white crystals.

mp. 120.3-120.7° C.

¹H-NMR (CDCl₃) δ: 1.19-1.26 (5H, m), 2.75-2.89 (2H, m), 3.14 (1H, dd,J=12.5 & 6.5 Hz), 4.11 (2H, q, J=7.1 Hz), 7.37 (1H, d, J=4.9 Hz),7.60-7.70 (3H, m), 8.42 (1H, s), 8.56 (1H, d, J=7.9 Hz), 8.63 (1H, d,J=5.1 Hz).

IR(KBr): 1728, 1661, 1599, 1572, 1537, 1439, 1298 cm⁻¹.

Elemental Analysis for C₁₉H₁₈N₂O₃S

Calcd. C, 64.39; H, 5.12; N, 7.90.

Found C, 64.31; H, 5.26; N, 7.69.

Reference Example 149

Ethyl 3-(2-cyano-4-pyridyl)-2-methylpropionate

Ethyl 2-methyl-3-(4-pyridyl)propionate (5.9 g, 30.5 mmol) was dissolvedin ethyl acetate (25 ml) and 3-Chloroperbenzoic acid (ca. 77%, 7.5 g,33.4 mmol) was added thereto. The reaction mixture was stirred at roomtemperature for 14 hrs and subjected to a silica gel (120 g) columnchromatography. The fractions eluted with ethyl acetate-ethanol (3:1,v/v) were collected and concentrated. The residue was dissolved inacetonitrile (18 ml), and trimethylsilyl cyanide (4.5 g, 45.0 mmol) andN,N-dimethylcarbamoyl chloride (3.5 g, 32.5 mmol) were added thereto.The reaction mixture was stirred at room temperature for 18 hrs andcombined with ethyl acetate and water. The organic layer wassuccessively washed with saturated aqueous sodium hydrogen carbonatesolution and saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated, and the residue was subjected to a silicagel (50 g) column chromatography. The fractions eluted withhexane-ethylacetate (4:1, v/v) were collected and concentrated to givethe titled compound (3.7 g, 76%).

¹H-NMR (CDCl₃) δ: 1.20 (3H, t, J=7.1 Hz), 1.22 (3H, d, J=6.7 Hz),2.71-2.82 (2H, m), 3.06 (1H, m), 4.10 (2H, q, J=7.1 Hz), 7.34 (1H, d,J=5.0 Hz), 7.54 (1H, s), 8.60 (1H, d, J=5.0 Hz).

Reference Example 150

N,N-Dimethyl-2-(2-methyl-4-pyridyl)ethenamine

n-Butyl lithium in hexane (1.6 M, 35 ml, 56 mmol) was added dropwise toa solution of 2,4-lutidine (5.0 g, 46 mmol) in tetrahydrofuran (50 ml)at −78° C., and the mixture was stirred at the same temperature for 30minutes. Successively, diethylamine (5.1 g, 69 mmol) was added to themixture, and the mixture was stirred at −78° C., and the mixture wasstirred at the same temperature for 30 minutes. Furthermore, DMF (6.8 g,93 mmol) was added to the mixture at −78° C., and the mixture wasstirred at the same temperature for 1 hr. The reaction mixture wascombined with aqueous ammonium chloride solution and extracted withethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated togive the titled compound (7.5 g, 99%).

¹H-NMR (CDCl₃) δ: 2.43 (3H, s), 2.86 (6H, s), 4.96 (1H, m), 6.76-6.84(2H, m), 6.99 (1H, d, J=13.7 Hz), 8.16 (1H, m).

Reference Example 151

2-Methylisonicotinaldehyde

A solution of N,N-dimethyl-2-(2-methyl-4-pyridyl)ethenamine (6.4 g, 39mmol) in methanol (25 ml) was added dropwise to a mixture of sodiumperiodate (25.2 g, 117 mmol) and methanol (25 ml) at room temperature.The mixture was stirred at the same temperature for 1 hr. Theprecipitates were filtered off, and the filtrate was concentrated. Theresidue was combined with water and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over magnesiumsulfate. The solvent was evaporated to give the titled compound (3.7 g,78%).

¹H-NMR (CDCl₃) δ: 2.68 (3H, s), 7.51 (1H, d, J=4.9 Hz), 7.56 (1H, s),8.76 (1H, d, J=4.9 Hz), 10.05 (1H, s).

Reference Example 152

tert-Butyl (E)-3-(2-methyl-4-pyridyl)-2-propenoate

A solution of tert-butyl diethylphosphonoacetate (12.4 g, 49 mmol) intetrahydrofuran (30 ml) was added dropwise to a mixture of sodiumhydride (60% in oil, 2.3 g, 57 mmol) and tetrahydrofuran (100 ml) at 0°C., and the mixture was stirred at the same temperature for 30 minutes.Successively, a solution of 2-methylisonicotinaldehyde (5.0 g, 41 mmol)in tetrahydrofuran (20 ml) was added to the mixture at 0° C., and themixture was stirred at room temperature for 1 hr. The reaction mixturewas combined with water and extracted with ethyl acetate. The organiclayer was washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated, and the residue was subjected to asilica gel column chromatography. The fractions eluted with ethylacetate-hexane (2:3, v/v) were collected and concentrated to give thetitled compound (4.4 g, 48%).

¹H-NMR (CDCl₃) δ: 1.53 (9H, s), 2.57 (3H, s), 6.49 (1H, d, J=16.1 Hz),7.16 (1H, d, J=5.1 Hz), 7.20 (1H, s), 7.46 (1H, d, J=16.1 Hz), 8.51 (1H,d, J=5.1 Hz).

Reference Example 153

tert-Butyl 3-(2-methyl-4-pyridyl)propanoate

tert-Butyl (E)-3-(2-methyl-4-pyridyl)-2-propenoate (4.4 g, 20 mmol) wasdissolved in methanol (100 ml), and 10% palladium-carbon (0.45 g) wasadded thereto. The mixture was stirred under hydrogen atmosphere for 3hrs. Palladium-carbon was filtered off, and the filtrate wasconcentrated to give the titled compound (4.4 g, 99%).

¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 2.52 (3H, s), 2.54 (2H, t, J=7.5 Hz),2.86 (2H, t, J=7.5 Hz), 6.94 (1H, d, J=5.1 Hz), 7.00 (1H, s), 8.37 (1H,d, J=5.1 Hz).

Reference Example 154

tert-Butyl 3-(2-methyl-4-pyridyl)propanoate N-oxide

tert-Butyl 3-(2-methyl-4-pyridyl)propanoate (4.3 g, 19 mmol) and3-chloroperbenzoic acid (77%, 5.3 g, 23 mmol) were dissolved in ethylacetate (100 ml), and the mixture was stirred at room temperature for 20hrs. The solvent was evaporated, and the residue was subjected to asilica gel column chromatography. The fractions eluted withethanol-ethyl acetate (1:3, v/v) were collected and concentrated to givethe titled compound (4.4 g, 94%)

¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 2.50 (3H, s), 2.54 (2H, t, J=7.3 Hz),2.86 (2H, t, J=7.3 Hz), 6.99 (1H, d, J=6.6 Hz), 7.10 (1H, s), 8.17 (1H,d, J=6.6 Hz).

Reference Example 155

tert-Butyl 3-(2-cyano-6-methyl-4-pyridyl)propanoate

tert-Butyl 3-(2-methyl-4-pyridyl)propanoate N-oxide (4.4 g, 18 mmol) wasdissolved in acetonitrile (150 ml), and trimethylsilyl cyanide (3.7 g,37 mmol) and N,N-dimethylcarbamoyl chloride (3.0 g, 28 mmol) were addedthereto. The mixture was stirred at room temperature for 48 hrs. Thesolvent was evaporated, and the residue was combined with water andextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over magnesium sulfate. The solvent wasevaporated, and the residue was subjected to a silica gel columnchromatography. The fractions eluted with ethyl acetate-hexane (1:5,v/v) were collected and concentrated to give the titled compound (2.8 g,62%).

¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 2.56 (2H, t, J=7.4 Hz), 2.56 (3H, s),2.91 (2H, t, J=7.4 Hz), 7.21 (1H, s), 7.37 (1H, s)

Example 319

tert-Butyl 3-[2-methyl-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate

tert-Butyl 3-(2-cyano-6-methyl-4-pyridyl)propanoate (1.2 g, 4.8 mmol)and methyl thiosalicylate (1.6 g, 9.9 mmol) were dissolved in toluene(10 ml), and triethylamine (4.0 ml, 28.6 mmol) was added thereto. Themixture was refluxed for 24 hrs. The solvent was evaporated, and theresidue was subjected to a silica gel column chromatography. Thefractions eluted with ethyl acetate-hexane (1:2, v/v) were collected,concentrated and recrystallized from tetrahydrofuran-hexane to give thetitled compound (1.2 g, 66%)

mp. 129.4-130.5° C.

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 2.62 (2H, t, J=7.5 Hz), 2.64 (3H, s),2.97 (2H, t, J=7.5 Hz), 7.25 (1H, s), 7.59-7.68 (3H, m), 8.23 (1H, s),8.55 (1H, m). IR: 2976, 2932, 1728, 1660, 1572, 1537, 1493, 1367, 1292,1151, 1097 cm⁻¹.

Elemental Analysis for C₂₁H₂₂N₂O₃S

Calcd. C, 65.95; H, 5.80; N, 7.32.

Found C, 65.89; H, 5.89; N, 7.14.

Example 320

tert-Butyl 3-[2-(7-chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-6-methyl-4-pyridyl]propanoate

tert-Butyl 3-(2-cyano-6-methyl-4-pyridyl)propanoate (1.6 g, 6.5 mmol)and 4-chlorothiosalicylic acid (2.4 g, 13.1 mmol) were dissolved inpyridine (20 ml). The mixture was refluxed for 24 hrs. The solvent wasevaporated, and residue was subjected to a silica gel columnchromatography. The fractions eluted with hexane-ethyl acetate (2:1,v/v) were collected, concentrated and recrystallized from hexane-ethylacetate to give the titled compound (1.2 g, 46%) as pale yellowcrystals.

mp. 186.4-187.6° C.

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 2.61 (2H, t, J=7.5 Hz), 2.63 (3H, s),2.97 (2H, t, J=7.5 Hz), 7.26 (1H, s), 7.56 (1H, dd, J=1.9, 8.4 Hz), 7.60(1H, d, J=1.9 Hz), 8.20 (1H, s), 8.47 (1H, d, J=8.4 Hz).

IR: 2976, 1726, 1664, 1585, 1564, 1535, 1379, 1284, 1151, 1095 cm⁻¹.

Elemental Analysis for C₂₁H₂₁N₂O₃SCl

Calcd. C, 60.50; H, 5.08; N, 6.72.

Found C, 60.45; H, 5.20; N, 6.59.

Example 321

3-[2-Methyl-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]pr opionic acid

tert-Butyl 3-[2-methyl-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate (0.96 g, 2.5 mmol) was dissolved in trifluoroacetic acid (8ml), and the mixture was stirred at 0° C. for 2 hrs. The solvent wasevaporated, and the residue was recrystallized from diisopropylether-ethanol to give the titled compound (0.74 g, 90%) as whitecrystals.

mp. 233.2-234.7° C.

¹H-NMR (DMSO-d₆) δ: 2.57 (3H, s), 2.66 (2H, t, J=7.3 Hz), 2.95 (2H, t,J=7.3 Hz), 7.49 (1H, s), 7.71 (1H, m), 7.81 (1H, m), 7.92 (1H, d, J=7.9Hz), 8.05 (1H, s), 8.34 (1H, d, J=7.9 Hz), 12.30 (1H, br s).

IR: 3051, 1722, 1518, 1439, 1307, 1188 cm⁻¹.

Elemental Analysis for C₁₇H₁₄N₂O₃S

Calcd. C, 62.56; H, 4.32; N, 8.58.

Found C, 62.52; H, 4.24; N, 8.43.

Example 322

3-[2-(7-Chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-6-methyl-4-pyridyl]propionic acid

tert-Butyl 3-[2-(7-chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-6-methyl-4-pyridyl]propanoate (0.90 g, 2.5 mmol) was dissolved in trifluoroaceticacid (8 ml), and the mixture was stirred at 0° C. for 2 hrs. The solventwas evaporated, and the residue was recrystallized from diisopropylether-ethanol to give the titled compound (0.74 g, 82%) as pale yellowcrystals.

mp. 273.5° C. (decomposed)

¹H-NMR (DMSO-d₆) δ: 2.57 (3H, s), 2.66 (2H, t, J=7.3 Hz), 2.95 (2H, t,J=7.3 Hz), 7.51 (1H, s), 7.74 (1H, dd, J=2.0, 8.6 Hz), 8.04 (1H, s),8.15 (1H, d, J=2.0 Hz), 8.31 (1H, d, J=8.5 Hz), 12.22 (1H, br s). IR:3084, 3024, 1724, 1628, 1560, 1523, 1302, 1182 cm⁻¹.

Elemental Analysis for C₁₇H₁₃N₂O₃SCl

Calcd. C, 56.59; H, 3.63; N, 7.76.

Found C, 56.48; H, 3.60; N, 7.62.

Reference Example 156

N-(2-Chloroethyl)-N′-(4-pyridyl)urea

2-Chloroethylisocyanate (10.0 g, 94 mmol) was added dropwise to amixture of 4-aminopyridine (6.0 g, 63 mmol) and toluene (40 mL) at 0°C., and the mixture was stirred at room temperature for 6 hrs. Theprecipitates were collected by filtration and washed with diisopropylether to give the titled compound (11.1 g, 87%) as white crystals.

¹H-NMR (DMSO-d₆) δ: 3.43 (2H, m), 3.66 (2H, t, J=6.1 Hz), 6.67 (1H, t,J=5.6 Hz), 7.37 (2H, d, J=6.2 Hz), 8.29 (2H, d, J=6.2 Hz), 9.19 (1H, s).

Reference Example 157

1-(4-Pyridyl)-2-imidazolidinone

Sodium hydride (60% in oil, 2.4 g, 60 mmol) was added to a mixture ofN-(2-chloroethyl)-N′-(4-pyridyl)urea (11.1 g, 55 mmol), tetrahydrofuran(40 ml) and DMF (40 ml) at 0° C., and the mixture was stirred at roomtemperature for 2 hrs. The reaction mixture was combined with methanol.The solvent was evaporated, and the residue was combined with water andextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over magnesium sulfate. The residue wasrecrystallized from tetrahydrofuran-hexane to give the titled compound(2.4 g, 27%) as white crystals.

¹H-NMR (CDCl₃) δ: 3.64 (2H, t, J=7.2 Hz), 3.94 (2H, t, J=7.2 Hz), 5.39(1H, br s), 7.48 (2H, d, J=5.0 Hz), 8.47 (2H, d, J=5.0 Hz).

Reference Example 158

tert-Butyl [2-oxo-3-(4-pyridyl)-1-imidazolidinyl]acetate

Sodium hydride (60% in oil, 0.40 g, 10.1 mmol) was added to a mixture of1-(4-pyridyl)-2-imidazolidinone (1.5 g, 9.2 mmol) and DMF (20 ml) at 0°C., and the mixture was stirred at room temperature for 30 minutes.Successively, tert-butyl bromoacetate (2.2 g, 11.2 mmol) was added tothe mixture, and the mixture was stirred at room temperature for 2 hrs.The reaction mixture was combined with water and extracted with ethylacetate. The organic layer was washed with saturated brine and driedover magnesium sulfate. The solvent was evaporated, and the residue wassubjected to a silica gel column chromatography. The fractions elutedwith ethyl acetate-methanol (5:1, v/v) were collected, concentrated andrecrystallized from tetrahydrofuran-hexane to give the titled compound(1.7 g, 68%) as white crystals.

mp. 146.8-147.7° C.

¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 3.67 (2H, m), 3.87 (2H, m), 3.97 (2H,s), 7.48 (2H, m), 8.46 (2H, m).

IR: 2980, 2934, 1739, 1711, 1595, 1510, 1471, 1442, 1392, 1282, 1234,1153 cm⁻¹.

Elemental Analysis for C₁₄H₁₉N₃O₃

Calcd. C, 60.63; H, 6.91; N, 15.15.

Found C, 60.57; H, 6.92; N, 15.04.

Reference Example 159

tert-Butyl [2-oxo-3-(4-pyridyl)-1-imidazolidinyl]acetate N-oxide

tert-Butyl [2-oxo-3-(4-pyridyl)-1-imidazolidinyl]acetate (1.6 g, 5.9mmol) and 3-chloroperbenzoic acid (77%, 2.0 g, 8.9 mmol) were dissolvedin chloroform (30 ml), and the mixture was stirred at room temperaturefor 45 hrs. The solvent was evaporated, and the residue was subjected toa silica gel column chromatography. The fractions eluted withmethanol-ethyl acetate (2:3, v/v) were collected and concentrated togive the titled compound (1.6 g, 95%) as white crystals.

¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 3.69 (2H, m), 3.86 (2H, m), 3.96 (2H,s), 7.53 (2H, d, J=7.5 Hz), 8.13 (2H, d, J=7.5 Hz).

Reference Example 160

tert-Butyl [3-(2-cyano-4-pyridyl)-2-oxo-imidazolidinyl]acetate

tert-Butyl [2-oxo-3-(4-pyridyl)-1-imidazolidinyl]acetate N-oxide (1.6 g,5.6 mmol) was dissolved in nitroethane (50 ml), and trimethylsilylcyanide (1.1 g, 11.5 mmol) and N,N-dimethylcarbamoyl chloride (1.0 g,9.3 mmol) were added thereto. The mixture was stirred at roomtemperature for 14 hrs. The solvent was evaporated, and the residue wassubjected to a silica gel column chromatography. The fractions elutedwith ethyl acetate-hexane (4:1, v/v) were collected, concentrated andrecrystallized from ethyl acetate-hexane to give the titled compound(0.93 g, 54%) as pale yellow crystals.

mp. 139.0-140.1° C.

¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 3.70 (2H, m), 3.89 (2H, m), 3.98 (2H,s), 7.61 (1H, dd, J=2.3, 5.7 Hz), 8.00 (1H, d, J=2.3 Hz), 8.51 (1H, d,J=5.7 Hz).

IR: 2978, 2935, 2235, 1718, 1591, 1477, 1437, 1392, 1280, 1234, 1155cm⁻¹.

Elemental Analysis for C₁₅H₁₈N₄O₃

Calcd. C, 59.59; H, 6.00; N, 18.53.

Found C, 59.39; H, 6.00; N, 18.58.

Example 323

tert-Butyl (2-oxo-3-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]-1-imidazolidinyl]acetate

tert-Butyl [3-(2-cyano-4-pyridyl)-2-oxo-1-imidazolidinyl]acetate (0.80g, 2.6 mmol) and methyl thiosalicylate (1.33 g, 7.8 mmol) were dissolvedin toluene (6 ml), and triethylamine (2.0 ml, 14.3 mmol) was addedthereto. The mixture was refluxed for 8 hrs. The solvent was evaporated,and the residue was subjected to a silica gel column chromatography. Thefractions eluted with ethyl acetate-hexane (3:1, v/v) were collected,concentrated and recrystallized from tetrahydrofuran-hexane to give thetitled compound (0.68 g, 58%).

mp. 192.3-194.0° C.

¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 3.72 (2H, m), 4.00 (2H, s), 4.02 (2H,m), 7.60-7.69 (3H, m), 7.96 (1H, d, J=0.6 Hz), 8.53-8.56 (3H, m).

IR: 2978, 2932, 1738, 1714, 1660, 1593, 1572, 1537, 1477, 1435, 1280,1232, 1155 cm⁻¹.

Elemental Analysis for C₂₂H₂₂N₄O₄S

Calcd. C, 60.26; H, 5.06; N, 12.78.

Found C, 60.29; H, 5.12; N, 12.58.

Example 324

[2-Oxo-3-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]-1-imidazolidinyl]acetic acid

tert-Butyl [2-oxo-3-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]-1-imidazolidinyl]acetate (0.31 g, 0.70 mmol) was dissolved intrifluoroacetic acid (5 ml), and the mixture was stirred at 0° C. for 2hrs. The solvent was evaporated and the residue was recrystallized fromdiethyl ether-methanol to give the titled compound (0.22 g, 81%) aswhite crystals.

mp. 271.0-273.0° C.

¹H-NMR (DMSO-d₆) δ: 3.63 (2H, m), 4.00 (2H, m), 4.01 (2H, s), 7.72-7.91(4H, m), 8.35 (1H, d, J=7.7 Hz), 8.57-8.61 (2H, m), 12.93 (1H, br s).

IR: 2899, 1738, 1711, 1622, 1591, 1525, 1487, 1444, 1288, 1195 cm⁻¹.

Elemental Analysis for C₁₈H₁₄N₄O₄S·0.25H₂O

Calcd. C, 55.88; H, 3.78; N, 14.48.

Found C, 56.10; H, 3.76; N, 14.35.

Reference Example 161

1-Ethyl-3-(4-pyridyl)-2-imidazolidinone

Sodium hydride (60% in oil, 0.25 g, 6.3 mmol) was added to a mixture of1-(4-pyridyl)-2-imidazolidinone (0.94 g, 5.7 mmol) and DMF (15 ml) at 0°C., and the mixture was stirred at room temperature for 30 minutes.Successively, iodemethane (1.51 g, 9.6 mol) was added to the reactionmixture, and the mixture was stirred at room temperature for 2 hrs. Thereaction mixture was combined with water and extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated, and theresidue was crystallized from diisopropyl ether to give the titledcompound (0.71 g, 65%) as pale yellow crystals.

¹H-NMR (CDCl₃) δ: 1.19 (3H, t, J=7.2 Hz), 3.38 (2H, q, J=7.2 Hz), 3.55(2H, m), 3.80 (2H, m), 7.47 (2H, m), 8.44 (2H, m).

Reference Example 162

1-Ethyl-3-(4-pyridyl)-2-imidazolidinone N-oxide

1-Ethyl-3-(4-pyridyl)-2-imidazolidinone (0.71 g, 3.7 mmol) and3-chloroperbenzoic acid (77%, 1.67 g, 7.4 mmol) were dissolved in ethylacetate (20 ml), and the mixture was stirred at room temperature for 40hrs. The solvent was evaporated, and the residue was subjected to asilica gel column chromatography. The fractions eluted withmethanol-ethyl acetate (2:3, v/v) were collected and concentrated togive the titled compound (0.57 g, 73%) as white crystals.

¹H-NMR (CDCl₃) δ: 1.19 (3H, t, J=7.2 Hz), 3.38 (2H, q, J=7.2 Hz), 3.56(2H, m), 3.81 (2H, m), 7.54 (2H, d, J=7.6 Hz), 8.13 (2H, d, J=7.6 Hz).

Reference Example 163

4-(3-Ethyl-2-oxo-1-imidazolidinyl)-2-pyridinecarbonitrile

1-Ethyl-3-(4-pyridyl)-2-imidazolidinone N-oxide (0.56 g, 2.7 mmol) wasdissolved in nitroethane (20 ml), and trimethylsilyl cyanide (0.55 g,5.5 mmol) and N,N-dimethylcarbamoyl chloride (0.44 g, 4.1 mmol) wereadded thereto. The mixture was stirred at room temperature for 20 hrs.The solvent was evaporated, and the residue was subjected to a silicagel column chromatography. The fractions eluted with ethylacetate-hexane (5:1, v/v) were collected, concentrated andrecrystallized from tetrahydrofuran-hexane to give the titled compound(0.17 g, 29%) as white crystals.

¹H-NMR (CDCl₃) δ: 1.20 (3H, t, J=7.2 Hz), 3.40 (2H, q, J=7.2 Hz), 3.60(2H, m), 3.82 (2H, m), 7.60 (1H, dd, J=2.0, 5.7 Hz), 8.00 (1H, d, J=2.0Hz), 8.49 (1H, d, J=5.7 Hz).

Example 325

2-[4-(3-Ethyl-2-oxo-1-imidazolidinyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one

4-(3-Ethyl-2-oxo-1-imidazolidinyl)-2-pyridinecarbonit rile (0.16 g, 0.76mmol) and methyl thiosalicylate (0.42 g, 2.5 mmol) was dissolved intoluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto.The mixture was refluxed for 9 hrs. The solvent was evaporated, and theresidue was subjected to a silica gel column chromatography. Thefractions eluted with ethyl acetate were collected, concentrated andrecrystallized from tetrahydrofuran-hexane to give the titled compound(0.14 g, 51%) as white crystals.

mp. 211.5-213.0° C.

¹H-NMR (CDCl₃) δ: 1.21 (3H, t, J=7.2 Hz), 3.40 (2H, q, J=7.2 Hz), 3.60(2H, m), 3.97 (2H, m), 7.60-7.71 (3H, m), 7.93 (1H, d, J=2.1 Hz),8.52-8.58 (3H, m).

IR: 3495, 2976, 1707, 1653, 1591, 1527, 1479, 1437, 1273, 991 cm⁻¹.

Elemental Analysis for C₁₆H₁₆N₄O₂S

Calcd. C, 61.35; H, 4.58; N, 15.90.

Found C, 61.30; H, 4.71; N, 15.84.

Example 326

2-(6-Oxo-1,6-dihydro-2-pyridyl)-4H-1,3-benzothiazine-4-one

2-(6-(Benzyloxy)-2-pyridyl)-4H-1,3-benzothiazine-4-on e (0.15 g, 0.43mmol) was dissolved in trifluoroacetic acid (10 ml), and the mixture wasstirred at room temperature for 15 hrs. The solvent was evaporated, andthe residue was recrystallized from chloroform-hexane to give the titledcompound (0.07 g, 69%).

mp. 214.2-215.3° C.

¹H-NMR (CDCl₃) δ: 6.89 (1H, d, J=9.1 Hz), 7.22 (1H, d, J=6.9 Hz),7.52-7.57 (2H, m), 7.65-7.75 (2H, m), 8.52 (1H, d, J=8.1 Hz), 9.85 (1H,br s).

IR: 3437, 1666, 1645, 1606, 1523, 1440, 1298, 806 cm⁻¹.

Elemental Analysis for C₁₃H₈N₂O₂S

Calcd. C, 60.93; H, 3.15; N, 10.93.

Found C, 60.72; H, 3.07; N, 10.80.

Example 327

tert-Butyl 3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-3-pyridyl]propanoate

tert-Butyl 3-(6-cyano-3-pyridyl)propanoate (0.46 g, 1.97 mmol) andmethyl thiosalicylate (0.50 g, 2.96 mmol) were dissolved in toluene (30ml), and triethylamine (0.55 ml, 3.94 mmol) was added thereto. Themixture was refluxed for 18 hrs. The solvent was evaporated, and theresidue was recrystallized from ethanol to give the titled compound(0.71 g, 98%) as white crystals.

mp. 160.0-161.0° C.

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 2.62 (2H, t, J=7.5 Hz), 3.03 (2H, t,J=7.4 Hz), 7.59-7.68 (3H, m), 7.74-7.77 (1H, m), 8.47 (1H, d, J=8.2 Hz),8.53-8.56 (1H, m), 8.60 (1H, d, J=1.7 Hz).

IR(KBr): 1722, 1658, 1591, 1572, 1531, 1435, 1363, 1307, 1282, 1159,1097, 1024, 935, 852, 748 cm⁻¹.

Elemental Analysis for C₂₀H₂₀N₂O₃S

Calcd. C, 65.20; H, 5.47; N, 7.60.

Found C, 65.17; H, 5.55; N, 7.54.

Example 328

3-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-3-pyridyl]propionic acid

tert-Butyl 3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-3-pyridyl]propanoate(0.21 g, 0.56 mmol) was dissolved in trifluoroacetic acid (5 ml), andthe mixture was stirred at room temperature for 0.5 hr. Diisopropylether was added to the reaction mixture to give crystals, which wererecrystallized from ethanol to give the titled compound (0.12 g, 68%) aswhite crystals.

mp. 232.2-232.4° C.

¹H-NMR (DMSO-d₆) δ: 2.67 (2H, t, J=7.5 Hz), 2.97 (2H, t, J=7.4 Hz), 7.72(2H, t, J=7.1 Hz), 7.80-7.86 (1H, m), 7.91 (1H, d, J=7.8 Hz), 7.97-8.00(1H, m), 8.28 (1H, d, J=8.1 Hz), 8.35 (1H, d, J=7.4 Hz), 8.71 (1H, d,J=1.6 Hz), 12.2 (1H, br s).

IR(KBr): 3514, 3024, 2706, 1712, 1699, 1635, 1568, 1518, 1460, 1442,1311, 1294, 1228, 1178, 1157, b1134, 1103, 1028, 947, 852, 752 cm⁻¹.

Elemental Analysis for C₁₆H₁₂N₂O₃S

Calcd. C, 61.53; H, 3.87; N, 8.97.

Found C, 61.41; H, 3.66; N, 8.87

Example 329

3-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-3-pyridyl]propanamide

3-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-3-pyridyl]propi onic acid (0.31 g,1.00 mmol), isobutyl chloroformate (0.22 ml, 1.50 mmol) andtriethylamine (0.22 ml, 1.50 mmol) were dissolved in THF (10 ml), andthe mixture was stirred under ice cooling condition for 1 hr. 25%aqueous ammonium solution was added to the mixture, and the mixture wasstirred under ice cooling condition for 0.5 hr. The obtainedprecipitates were recrystallized from ethanol to give the titledcompound (0.17 g, 55%) as white crystals.

mp. 247.5-247.8° C.

¹H-NMR (DMSO-d₆) δ: 2.47 (2H, t, J=7.4 Hz), 2.96 (2H, t, J=7.4 Hz), 6.83(1H, br s), 7.33 (1H, br s), 7.70-7.75 (1H, m), 7.80-7.85 (1H, m),7.90-7.96 (2H, m), 8.28 (1H, d, J=8.0 Hz), 8.35 (1H, d, J=7.8 Hz), 8.67(1H, d, J=1.8 Hz).

IR(KBr): 3393, 3179, 1682, 1647, 1570, 1527, 1439, 1307, 1286, 1244,1203, 1286, 1244, 1203, 1128, 1099, 1068, 1032, 966, 945, 850, 756 cm⁻¹.

Elemental Analysis for C₁₆H₁₃N₃O₂S

Calcd. C, 61.72; H, 4.21; N, 13.50.

Found C, 61.64; H, 4.05; N, 13.23.

Example 330

3-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanamide

3-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propi onic acid (0.31 g,1.00 mmol), isobutyl chloroformate (0.22 ml, 1.50 mmol) andtriethylamine (0.22 ml, 1.50 mmol) were dissolved in THF (10 ml), andthe mixture was stirred under ice cooling condition for 1 hr. 25%aqueous ammonium solution was added to the mixture, and the mixture wasstirred under ice cooling condition for 0.5 hr. The obtainedprecipitates were recrystallized from ethanol to give the titledcompound (0.20 g, 65%) as white crystals.

mp. 236.3-236.5° C.

¹H-NMR (DMSO-d₆) δ: 2.62 (2H, t, J=7.3 Hz), 3.11 (2H, t, J=7.7 Hz), 6.84(1H, br s), 7.40 (1H, br s), 7.63 (1H, d, J=7.7 Hz), 7.73-7.75 (1H, m),7.84-7.86 (1H, m), 7.94 (1H, d, J=7.7 Hz), 8.00 (1H, t, J=7.8 Hz), 8.18(1H, d, J=7.7 Hz), 8.34-8.37 (1H, m).

IR(KBr): 3385, 3200, 1651, 1628, 1570, 1537, 1440, 1298, 1126, 1095,1064, 1028, 995, 815, 548 cm⁻¹.

Elemental Analysis for C₁₆H₁₃N₃O₂S

Calcd. C, 61.72; H, 4.21; N, 13.50.

Found C, 61.42; H, 4.02; N, 13.28.

Example 331

3-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanamide

3-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propi onic acid (0.31 g,1.00 mmol), isobutyl chloroformate (0.22 ml, 1.50 mmol) andtriethylamine (0.22 ml, 1.50 mmol) were dissolved in THF (10 ml), andthe mixture was stirred under ice cooling condition for 1 hr. 25%aqueous ammonium solution was added to the mixture, and the mixture wasstirred under ice cooling condition for 0.5 hr. The obtainedprecipitates were recrystallized from ethanol to give the titledcompound (0.15 g, 49%) as white crystals.

mp. 237.0-239.7° C.

¹H-NMR (DMSO-d₆) δ: 2.48 (2H, t, J=7.7 Hz), 2.99 (2H, t, J=7.4 Hz), 6.83(1H, br s), 7.36 (1H, br s), 7.61-7.62 (1H, m), 7.73 (1H, t, J=7.2 Hz),7.84 (1H, t, J=7.7 Hz), 7.84 (1H, t, J=7.7 Hz), 7.92 (1H, d, J=7.9 Hz),8.23 (1H, s), 8.36 (1H, d, J=7.8 Hz), 8.68 (1H, d, J=4.9 Hz).

IR(KBr): 3404, 3300, 3200, 1662, 1599, 1572, 1537, 1439, 1408, 1304,1280, 1230, 1165, 1095, 1068, 1030, 999, 835, 742 cm⁻¹.

Elemental Analysis for C₁₆H₁₃N₃O₂S

Calcd. C, 61.72; H, 4.21; N, 13.50.

Found C, 61.66; H, 4.26; N, 13.48.

Example 332

2,2-Dimethyl-3-hydroxy-3-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propionic acid

2-(Trimethylsilyl)ethyl2,2-dimethyl-3-hydroxy-3-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propionate (0.11 g, 0.24 mmol) was dissolved intetrahydrofuran (2 ml), and 1.0 M tetrabutylammonium fluoride intetrahydrofuran (0.58 ml, 0.58 mmol) was added thereto. The reactionmixture was stirred for 2 hrs and concentrated under reduced pressure.Trifluoroacetic acid (1.5 ml) was added to the residue, and the mixturewas stirred at room temperature for 13 hrs. Diisopropyl ether was addedto the mixture. The precipitated solid was collected by filtration andrecrystallized from ethanol-hexane to give the titled compound (0.044 g,51%) as white crystals.

mp. 235.3-235.8° C.

IR: 3358, 3073, 1714, 1693, 1682, 1591, 1631, 1523, 1467 cm⁻¹.

¹H-NMR (DMSO-d₆) δ: 0.96 (3H, s), 1.09 (3H, s), 4.99 (1H, d, J=4.3 Hz),5.99 (1H, d, J=4.3 Hz), 7.65 (1H, d, J=4.4 Hz), 7.74 (1H, t, J=7.5 Hz),7.84 (1H, t, J=7.0 Hz), 7.92 (1H, m), 8.32 (1H, s), 8.37 (1H, d, J=7.8Hz), 8.74 (1H, d, J=4.9 Hz).

Reference Example 164

2-(Trimethylsilyl)ethyl2,2-dimethyl-3-hydroxy-3-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propionate

2-(Trimethylsilyl)ethyl 2,2-dimethyl-3-(2-cyano-4-pyridyl)propionate(0.53 g, 1.7 mmol) and methyl thiosalicylate (0.44 g, 2.6 mmol) weredissolved in toluene (2 ml), and triethylamine (0.41 ml, 3.0 mmol) wasadded thereto. The reaction mixture was refluxed for 50 hrs andsubjected to a silica gel (30 g) column chromatography. The fractionseluted with hexane-ethyl acetate (3:1, v/v) were collected andconcentrated to give the titled compound (0.12 g, 16%) as whitecrystals.

¹H-NMR (CDCl₃) δ: 0.05 (9H, s), 1.02 (2H, m), 1.16 (3H, s), 1.19 (3H,s), 3.65 (1H, d, J=4.4 Hz), 4.25 (2H, m), 5.01 (1H, d, J=4.4 Hz),7.57-7.70 (4H, m), 8.45 (1H, s), 8.55 (1H, d, J=8.1 Hz), 8.70 (1H, d,J=4.7 Hz)

Reference Example 165

2-(Trimethylsilyl)ethyl 2,2-dimethyl-3-(2-cyano-4-pyridyl)propionate

2-(Trimethylsilyl)ethyl 2,2-dimethyl-3-hydroxy-3-(4-pyridyl)propionate(0.60 g, 2.0 mmol) was dissolved in ethyl acetate (4 ml), and3-chloroperbenzoic acid (ca. 77%, 0.50 g, 2.2 mmol) was added thereto.The reaction mixture was stirred at room temperature for 16 hrs andsubjected to a silica gel (35 g) column chromatography. The fractionseluted with ethyl acetate-ethanol (4:1, v/v) were collected andconcentrated. The residue was dissolved in acetonitrile (4 ml), andtrimethylsilyl cyanide (0.39 g, 3.9 mmol) and N,N-dimethylcarbamoylchloride (0.38 g, 3.5 mmol) were added thereto. The reaction mixture wasstirred at room temperature for 50 hrs and combined with ethyl acetateand water. The organic layer was successively washed with saturatedaqueous sodium hydrogen carbonate solution, 1 N hydrochloric acid andsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated, and the residue was subjected to a silica gel (20 g)column chromatography. The fractions eluted with hexane-ethyl acetate(3:1, v/v) were collected and concentrated to give the titled compound(0.54 g, 85%).

¹H-NMR (CDCl₃) δ: 0.05 (9H, s), 0.97 (2H, m), 0.98 (3H, s), 1.16 (3H,s), 4.16 (2H, m), 5.01 (1H, s), 7.44 (1H, d, J=5.4 Hz), 7.64 (1H, s),8.64 (1H, d, J=5.4 Hz).

Reference Example 166

2-(Trimethylsilyl)ethyl 2,2-dimethyl-3-hydroxy-3-(4-pyridyl)propionate

1.6 M n-butyl lithium in hexane (14.0 ml, 22.4 mmol) was added to asolution of diisopropylamine (2.3 g, 22.4 mmol) in tetrahydrofuran (15ml) under ice cooling condition, and the mixture was stirred for 30minutes. The reaction mixture was cooled to −78° C., and a solution of2-(trimethylsilyl)ethyl isobutyrate (4.0 g, 21.2 mmol) intetrahydrofuran (5 ml) was added dropwise to the mixture. The reactionmixture was stirred for 45 minutes. Successively, a solution of4-pyridinecarbaldehyde (2.5 g, 23.3 mmol) in tetrahydrofuran (10 ml) wasadded to the mixture, and the mixture was stirred with warming from −78°C. to room temperature for 2.5 hrs. The reaction mixture was combinedwith saturated aqueous ammonium chloride solution and extracted withethylacetate. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated, andthe residue was subjected to a silica gel (100 g) column chromatography.The fraction eluted with hexane-ethyl acetate (3:1, v/v) were collectedand concentrated to give the titled compound (3.2 g, 51%) as a colorlessoil.

¹H-NMR (CDCl₃) δ: 0.05 (9H, s), 1.00 (2H, m), 1.12 (3H, s), 1.14 (3H,s), 3.60 (1H, d, J=4.4 Hz), 4.21 (2H, m), 4.86 (1H, d, J=4.4 Hz), 7.24(2H, d, J=6.0 Hz), 8.55 (2H, d, J=6.0 Hz)

Example 333

2,2-Dimethyl-3-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridy l]propionate

2-(Trimethylsilyl)ethyl2,2-dimethyl-3-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridy l]propionate(0.41 g, 0.93 mmol) was dissolved in tetrahydrofuran (5 ml), and 1.0 Mtetrabutylammonium fluoride in tetrahydrofuran (2.2 ml, 2.2 mmol) wasadded thereto. The reaction mixture was stirred for 2 hrs. The reactionmixture was concentrated under reduced pressure. Trifluoroacetic acid(1.5 ml) was added to the mixture, and the mixture was stirred at roomtemperature for 13 hrs. Diisopropyl ether was added to the reactionmixture to precipitate solid, which was collected by filtration andrecrystallized from ethanol-hexane to give the titled compound (0.10 g,32%) as white crystals.

mp. 212.3-212.9° C.

IR: 3514, 3056, 1714, 1620, 1520, 1470, 1318 cm⁻¹.

¹H-NMR (DMSO-d₆) δ: 1.15 (6H, s), 3.00 (2H, s), 7.54 (1H, d, J=4.9 Hz),7.76 (1H, t, J=7.9 Hz), 7.84 (1H, t, J=7.2 Hz), 7.92 (1H, m), 8.18 (1H,s), 8.37 (1H, d, J=7.8 Hz), 8.71 (1H, d, J=4.9 Hz), 12.52 (1H, br s).

Reference Example 167

2-(Trimethylsilyl)ethyl2,2-dimethyl-3-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridy l]propionate

2-(Trimethylsilyl)ethyl 2,2-dimethyl-3-(2-cyano-4-pyridyl)propionate(0.68 g, 2.2 mmol) and methyl thiosalicylate (0.60 g, 3.6 mmol) weredissolved in toluene (2.5 ml), and triethylamine (0.56 ml, 4.0 mmol) wasadded thereto. The reaction mixture was refluxed for 16 hrs andsubjected to a silica gel (30 g) column chromatography. The fractionseluted with hexane-ethyl acetate (5:1, v/v) were collected andconcentrated to give the titled compound (0.52 g, 53%) as whitecrystals.

¹H-NMR (CDCl₃) δ: 0.03 (9H, s), 0.99 (2H, m), 1.23 (6H, s), 2.98 (2H,s), 4.18 (2H, m), 7.34 (1H, d, J=4.9 Hz), 7.60-7.71 (3H, m), 8.35 (1H,s), 8.55 (1H, d, J=8.0 Hz), 8.61 (1H, d, J=4.9 Hz).

Reference Example 168

2-(Trimethylsilyl)ethyl 2,2-dimethyl-3-(2-cyano-4-pyridyl)propionate

2-(Trimethylsilyl)ethyl 2,2-dimethyl-3-(4-pyridyl)propionate (0.77 g,2.8 mmol) was dissolved in ethyl acetate (4 ml), and 3-chloroperbenzoicacid (ca. 77%, 0.68 g, 3.0 mmol) was added thereto. The reaction mixturewas stirred at room temperature for 5 hrs and subjected to a silica gel(35 g) column chromatography. The fractions eluted with ethylacetate-ethanol (4:1, v/v) were collected and concentrated. The residuewas dissolved in acetonitrile (6 ml), and trimethylsilyl cyanide (0.49g, 4.9 mmol) and N,N-dimethylcarbamoyl chloride(0.45 g, 4.2 mmol) wereadded thereto. The reaction mixture was stirred at room temperature for14 hrs and combined with ethyl acetate and water. The organic layer wassuccessively washed with saturated aqueous sodium hydrogen carbonatesolution, 1 N hydrochloric acid and saturated brine and dried overmagnesium sulfate. The solvent was evaporated, and the residue wassubjected to a silica gel (30 g) column chromatography. The fractionseluted with hexane-ethyl acetate (5:1, v/v) were collected andconcentrated to give the titled compound (0.69 g, 91%).

¹H-NMR (CDCl₃) δ: 0.05 (9H, s), 0.97 (2H, m), 1.20 (6H, s), 2.90 (2H,s), 4.16 (2H, m), 7.30 (1H, d, J=5.0 Hz), 7.50 (1H, s), 8.59 (1H, d,J=5.0 Hz).

Reference Example 169

2-(Trimethylsilyl)ethyl 2,2-dimethyl-3-(4-pyridyl)propionate

4-Pyridinemethanol (1.0 g, 9.2 mmol) was dissolved in tetrahydrofuran(10 ml), and triethylamine (1.5 ml, 10.9 mmol) and methanesulfonylchloride (0.75 ml, 9.7 mmol) were successively added thereto under icecooling condition. The mixture was stirred for 1 hr to produce mesylate.On the other hand, diisopropylamine (0.89 g, 8.8 mmol) was dissolved intetrahydrofuran (10 ml), and 1.6 M n-butyl lithium in hexane (5.5 ml,8.8 mmol) was added thereto under ice cooling condition. The reactionmixture was stirred for 30 minutes and cooled to −78° C. A solution of2-(trimethylsilyl)ethyl isobutyrate (1.6 g, 8.3 mmol) in tetrahydrofuran(5 ml) was added dropwise to the mixture at −78° C., and the mixture wasstirred for 1 hr. Successively, a solution of the mesylate producedabove in tetrahydrofuran (10 ml) was added dropwise to the mixture at−78° C., and the mixture was stirred for 3 hrs while it was warmed toroom temperature. The reaction mixture was filtered to remove theinsolubles. The filtrate was combined with saturated aqueous ammoniumchloride solution and extracted with ethyl acetate. The organic layerwas washed with saturated brine and dried over magnesium sulfate. Thesolvent was evaporated, and the residue was subjected to a silica gel(30 g) column chromatography. The fractions eluted with hexane-ethylacetate (3:1, v/v) were collected and concentrated to give the titledcompound (0.77 g, 30%) as a colorless oil.

¹H-NMR (CDCl₃) δ: 0.03 (9H, s), 0.93 (2H, m), 1.18 (6H, s), 2.84 (2H,s), 4.15 (2H, m), 7.06 (2H, d, J=6.0 Hz), 8.48 (2H, d, J=6.0 Hz).

Example 334

tert-Butyl3-[2-(6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl)ethoxy]_(p) ropanoate

tert-Butyl 3-[(2-cyano-6-pyridyl)]ethoxypropanoate (2.76 g, 10 mmol) andmethyl thiosalicylate (2.02 g, 12 mmol) were dissolved in toluene (25ml), and triethylamine (1.81 ml, 13 mmol) was added thereto. The mixturewas refluxed under nitrogen atmosphere for 20 hrs. The solvent wasevaporated, and the residue was subjected to a silica gel columnchromatography. The titled compound (1.55 g, 38%) was given as crystalsfrom the fractions eluted with ethyl acetate-hexane (1:2, v/v).

mp. 67.7-68.5° C.

¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 2.48 (2H, t, J=6.4 Hz), 3.16 (2H, t,J=6.5 Hz), 3.74 (2H, t, J=6.4 Hz), 3.94 (2H, t, J=6.5H), 7.45 (1H, dd,J=0.7, 7.9 Hz), 7.52-7.66 (3H, m), 7.79 (1H, t, J=7.7 Hz), 8.36 (1H, dd,J=0.7, 7.9 Hz), 8.54 (1H, dd, J=1.2, 7.5 Hz).

IR(KBr): 1728, 1663, 1591, 1572, 1535, 1439, 1366, 1298, 1258, 1159,1113, 1098, 995 cm⁻¹.

Elemental Analysis for C₂₂H₂₄N₂O₄S·0.2H₂O

Calcd. C, 63.50; H, 5.91; N, 6.73.

Found C, 64.06; H, 5.86; N, 6.64.

Example 335

3-[2-(6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl)ethoxy]_(p) ropionicacid

A mixture of tert-butyl3-[2-(6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl)ethoxy]_(p) ropionate(0.41 g, 1.0 mmol) and trifluoroacetic acid (5 ml) was stirred at 0° C.for 2 hrs. The reaction mixture was concentrated under reduced pressure.The residue was recrystallized from ethyl acetate-hexane to give thetitled compound (0.30 g, 85%).

mp. 236.6-236.7° C.

¹H-NMR (CDCl₃) δ: 2.42 (2H, t, J=6.3 Hz), 3.09 (2H, t, J=6.6 Hz), 3.64(2H, t, J=6.3 Hz), 3.84 (2H, t, J=6.6 Hz), 7.47-7.89 (5H, m), 8.17 (1H,d, J=7.7 Hz), 8.33 (1H, dd, J=1.3, 7.9 Hz), 12.10 (1H, br).

IR(KBr): 3059, 1713, 1655, 1572, 1534, 1443, 1397, 1306, 1238, 1115,1084, 1059, 1032, 995, 924 cm⁻¹.

Elemental Analysis for C₁₈H₁₆N₂O₄S

Calcd. C, 60.66; H, 4.53; N, 7.86.

Found C, 60.22; H, 4.50; N, 7.66.

Example 336

tert-Butyl 3-[(6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl)methoxy]propanoate

tert-Butyl 3-[(2-cyano-6-pyridyl)]methoxypropanoate (2.62 g, 10 mmol)and methyl thiosalicylate (1.85 g, 11 mmol) were dissolved in toluene(30 ml), and triethylamine (1.70 ml, 12 mmol) were added thereto. Thereaction mixture was refluxed under nitrogen atmosphere for 15 hrs. Thesolvent was evaporated, and the residue was subjected to a silica gelcolumn chromatography. The titled compound (2.92 g, 71%) was given fromthe fraction eluted with ethyl acetate-hexane (1:2, v/v) andrecrystallized from ethyl acetate-isopropyl ether.

mp. 84.7-84.9° C.

¹H-NMR (CDCl₃) δ: 1.36 (9H, s), 2.51 (2H, t, J=6.2 Hz), 3.77 (2H, t,J=6.2 Hz), 4.64 (2, s), 7.42-7.61 (4H, m), 7.78 (1H, t, J=7.8 Hz), 8.27(1H, d, J=7.7 Hz), 8.38 (1H, d, J=7.8 Hz).

IR(KBr): 1730, 1667, 1574, 1537, 1441, 1368, 1163, 1096, 1065, 1030,995, 846, 802, 750 cm⁻¹.

Elemental Analysis for C₂₁H₂₂N₂O₄S

Calcd. C, 63.30; H, 5.56; N, 7.03.

Found C, 63.15; H, 5.44; N, 7.28.

Example 337

3-[(6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl)methoxy]pr opionic acid

A mixture of tert-butyl3-[(6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl)methoxy]pr opanoate(2.80 g, 6.8 mmol) and trifluoroacetic acid (15 ml) was stirred at 0° C.for 3 hrs. The mixture was concentrated under reduced pressure, and theresidue was crystallized from ethyl acetate-hexane to give the titledcompound (1.78 g, 74%), which was recrystallized from ethanol to giveprisms (1.66 g, 69%)

mp. 176.6-176.7° C.

¹H-NMR (CDCl₃) δ: 2.57 (2H, t, J=6.2 Hz), 3.79 (2H, t, J=6.2 Hz), 4.68(2H, s), 7.59-7.77 (3H, m), 7.89 (1H, d, J=7.4 Hz), 8.08 (1H, t, J=7.7Hz), 8.23 (1H, d, J=7.4 Hz), 8.32 (1H, dd, J=1.1, 7.8 Hz)

IR(KBr): 3063, 1738, 1647, 1590, 1570, 1526, 1477, 1437, 1304, 1273,1194, 1121, 1103, 1063, 1046, 995, 866, 802 cm⁻¹.

Elemental Analysis for C₁₇H₁₄N₂O₄S

Calcd. C, 59.64; H, 4.12; N, 8.18.

Found C, 59.60; H, 3.82; N, 8.07.

Example 338

tert-Butyl 3-[6-(8-methyl-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoate

A mixture of 3-methylthiosalicylic acid (2.52 g, 15 mmol), tert-butyl3-(6-cyano-2-pyridyl)propanoate (2.32 g, 10 mmol) and pyridine (30 ml)was refluxed under nitrogen atmosphere for 20 hrs and concentrated underreduced pressure. The residue was subjected to a silica gel (100 g)column chromatography. The titled compound (2.79 g, 73%) was given fromthe fractions eluted with hexane-ethyl acetate (2:1, v/v), which wererecrystallized from ethyl acetate-isopropyl ether.

mp. 109.9-110.0 oc

¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 2.61 (3H, s), 2.88 (2H, t, J=7.3 Hz),3.21 (2H, t, J=7.3 Hz), 7.42 (1H, d, J=7.7 Hz), 7.44-7.53 (2H, m), 7.80(1H, t, J=7.8 Hz), 8.38 (1H, d, J=7.8 Hz), 8.43 (1H, dd, J=2.6, 6.8 Hz).

IR(KBr): 2976, 1728, 1661, 1537, 1454, 1366, 1308, 1152, 1098, 993, 912,847, 814 cm⁻¹.

Elemental Analysis for C₂₁H₂₂N₂O₃S

Calcd. C, 65.95; H, 5.80; N, 7.32.

Found C, 65.96; H, 5.71; N, 7.24.

Example 339

tert-Butyl 3-[2-cyano-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-3-pyridyl]propanoate

tert-Butyl 3-(2,6-dicyano-3-pyridyl)propanoate (0.31 g, 1.20 mmol) andmethyl thiosalicylate (0.40 g, 2.40 mmol) were dissolved in toluene (30ml), and triethylamine (0.75 ml, 5.41 mmol) was added thereto. Themixture was refluxed for 18 hrs, and the solvent was evaporated. Theresidue was washed with hexane-ethyl acetate to give the titled compound(0.12 g, 25%) as white amorphous solid.

mp. 196.3-196.8° C.

¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 2.73 (2H, t, J=7.2 Hz), 3.25 (2H, t,J=7.1 Hz), 7.64-7.75 (3H, m), 7.99 (1H, d, J=8.2 Hz), 8.55 (1H, d, J=7.7Hz), 8.65 (1H, d, J=8.2 Hz).

IR(KBr): 2233, 1712, 1651, 1570, 1529, 1444, 1369, 1348, 1300, 1267,1161, 1138, 1084, 1064, 979, 856, 750 cm⁻¹.

Example 340

3-[2-Cyano-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-3-pyridyl]pro panoate

tert-Butyl 3-[2-cyano-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-3-pyridyl]propanoate (0.06 g, 0.15 mmol) was dissolved in trifluoroacetic acid (3ml), and the mixture was stirred at room temperature for 0.5 hr. Thereaction mixture was combined with diisopropyl ether to giveprecipitates, which were recrystallized from ethanol to give the titledcompound (0.037 g, 74%) as white crystals.

mp. 283.8° C. (decomposed)

¹H-NMR (DMSO-d₆) δ: 2.78 (2H, t, J=7.3 Hz), 3.15 (2H, t, J=7.2 Hz),7.72-7.78(1H, m), 7.83-7.88 (1H, m), 7.99 (1H, d, J=7.3 Hz), 8.30 (1H,d, J=8.3 Hz), 8.35-8.38 (1H, m), 8.54 (1H, d, J=8.3 Hz), 12.3 (1H, brs).

IR(KBr): 3078, 1732, 1620, 1614, 1591, 1568, 1518, 1442, 1429, 1315,1271, 1207, 1161, 1130, 1109, 1032, 989, 862, 752 cm⁻¹.

Fab Mass(M+1)=338.1 (theoretical value)=338.1

Example 341

tert-Butyl 3-[2-(methylthio)-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate

tert-Butyl 3-[2-cyano-6-(methylthio)-4-pyridyl]propanoate (0.70 g, 2.50mmol) and methyl thiosalicylate (0.84 g, 5.00 mmol) were dissolved intoluene (50 ml), and triethylamine (1.40 ml, 10.0 mmol) was addedthereto. The reaction mixture was refluxed for 18 hrs, and the solventwas evaporated. The residue was recrystallized from hexane-ethyl acetateto give the titled compound (0.59 g, 57%) as pale yellow crystals.

mp. 125.5-126.5° C.

¹H-NMR (CDCl₃) δ: 1.43 (9H, s), 2.60 (2H, t, J=7.4 Hz), 2.71 (3H, s),2.94 (2H, t, J=7.5 Hz), 7.28 (1H, s), 7.60-7.70 (3H, m), 8.09 (1H, s),8.54-8.57 (1H, m).

IR(KBr): 2974, 1726, 1660, 1593, 1572, 1537, 1439, 1392, 1365, 1294,1257, 1234, 1149, 1095, 1030, 864, 746 cm⁻¹.

Elemental Analysis for C₂₁H₂₂N₂O₃S₂

Calcd. C, 60.84; H, 5.35; N, 6.76.

Found C, 60.56; H, 5.43; N, 6.52.

Example 342

3-[2-(Methylthio)-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propionic acid

tert-Butyl 3-[2-(methylthio)-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate (0.12 g, 0.29 mmol) was dissolved in trifluoroacetic acid(5 ml), and the mixture was stirred at room temperature for 0.5 hr.Diisopropyl ether was combined with the reaction mixture to giveprecipitates, which were recrystallized from ethanol to give the titledcompound (0.09 g, 87%) as pale yellow crystals.

mp. 235.5-236.5° C.

¹H-NMR (DMSO-d₆) δ: 2.66 (2H, t, J=7.5 Hz), 2.67 (3H, s), 2.94 (2H, t,J=7.3 Hz), 7.56 (1H, s), 7.70-7.75 (1H, m), 7.80-7.85 (1H, m), 7.92-7.96(2H, m), 8.34-8.37 (1H, m), 12.2 (1H, br s).

IR(KBr): 3067, 1732, 1637, 1595, 1574, 1537, 1431, 1307, 1277, 1234,1190, 1180, 1163, 1101, 1016, 891, 866, 740 cm⁻¹

Elemental Analysis for C₁₇H₁₄N₂O₃S₂

Calcd. C, 56.96; H, 3.94; N, 7.82.

Found C, 56.77; H, 3.89; N, 7.64.

Example 343

tert-Butyl3-[2-(methylsulfinyl)-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate

tert-Butyl 3-[2-(methylthio)-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate (0.22 g, 0.53 mmol) was dissolved in chloroform (50 ml),and a solution of 3-chloroperbenzoic acid (77%, 0.12 g, 0.53 mmol) inchloroform (10 ml) was added dropwise thereto. The mixture was stirredat room temperature for 1 hr. The solvent was evaporated, and theresidue was recrystallized from hexane-ethyl acetate to give the titledcompound (0.17 g, 86%) as white crystals.

mp. 219.5-220.0° C.

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 2.70 (2H, t, J=7.5 Hz), 2.97 (3H, s),3.13 (2H, t, J=7.5 Hz), 7.59-7.72 (3H, m), 8.12 (1H, d, J=1.2 Hz), 8.47(1H, d, J=1.1 Hz), 8.55-8.58 (1H, m).

IR(KBr): 2976, 1722, 1662, 1589, 1572, 1537, 1439, 1367, 1292, 1147,1095, 1062, 1030, 738 cm⁻¹.

Elemental Analysis for C₂₁H₂₂N₂O₄S₂·0.25H₂O

Calcd. C, 57.98; H, 5.21; N, 6.44.

Found C, 58.08; H, 5.15; N, 6.25.

Example 344

3-[2-(methylsulfinyl)-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propionicacid

tert-Butyl3-[2-(methylsulfinyl)-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate(0.12 g, 0.28 mmol) was dissolved in trifluoroacetic acid (5 ml), andthe mixture was stirred at room temperature for 0.5 hr. Diisopropylether was combined with the reaction mixture to give precipitates, whichwere recrystallized from ethanol to give the titled compound (0.095 g,91%) as white crystals.

mp. 265.5-266.0° C.

¹H-NMR (DMSO-d₆) δ: 2.74 (2H, t, J=7.3 Hz), 2.93 (3H, s), 3.13 (2H, t,J=7.2 Hz), 7.75-7.78 (1H, m), 7.83-7.88 (1H, m), 7.96 (1H, d, J=7.4 Hz),8.12 (1H, d, J=1.1 Hz), 8.34-8.39 (1H, m), 12.3 (1H, br s).

IR(KBr): 2955, 1722, 1657, 1589, 1570, 1537, 1439, 1413, 1340, 1294,1221, 1176, 1155, 1126, 1097, 1068, 1018, 993, 877, 750 cm⁻¹

Elemental Analysis for C₁₇H₁₄N₂O₄S₂

Calcd. C, 54.53; H, 3.77; N, 7.48.

Found C, 54.38; H, 3.98; N, 7.28.

Example 345

tert-Butyl3-[2-(methylsulfonyl)-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate

tert-Butyl 3-[2-(methylthio)-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate (0.20 g, 0.48 mmol) was dissolved in chloroform (50 ml),and a solution of 3-chloroperbenzoic acid (77%, 0.22 g, 0.97 mmol) inchloroform (10 ml) was added dropwise thereto. The mixture was stirredat room temperature for 3 hrs. The solvent was evaporated, and theresidue was recrystallized from hexane-ethyl acetate to give the titledcompound (0.060 g, 28%) as white crystals.

mp. 223.0° C. (decomposed)

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 2.70 (2H, t, J=7.4 Hz), 3.15 (2H, t,J=7.3 Hz), 3.37 (3H, s), 7.62-7.74 (3H, m), 8.16 (1H, d, J=0.8 Hz),8.55-8.59 (1H, m), 8.63 (1H, d, J=0.8 Hz).

IR(KBr): 2976, 1720, 1664, 1591, 1570, 1535, 1439, 1367, 1306, 1292,1234, 1149, 1128, 1095, 1066, 1030, 960, 748 cm⁻¹.

Elemental Analysis for C₂₁H₂₂N₂O₅S₂

Calcd. C, 56.48; H, 4.97; N, 6.27.

Found C, 56.30; H, 5.00; N, 6.18.

Example 346

3-[2-(Methylsulfonyl)-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propionicacid

tert-Butyl3-[2-(methylsulfonyl)-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate(0.20 g, 0.45 mmol) was dissolved in trifluoroacetic acid (5 ml), andthe mixture was stirred at room temperature for 0.5 hr. Diisopropylether was combined with the reaction mixture to give precipitates, whichwere recrystallized from ethanol to give the titled compound (0.11 g,63%) as pale yellow crystals.

mp. 305.5-306.0° C.

¹H-NMR (DMSO-d₆) δ: 2.75 (2H, t, J=7.2 Hz), 3.15 (2H, t, J=7.1 Hz), 3.45(3H, s), 7.76-7.79 (1H, m), 7.84-7.89 (1H, m), 7.99 (1H, d, J=7.6 Hz),8.28 (1H, d, J=0.9 Hz), 8.37-8.40 (1H, m), 8.52 (1H, d, J=0.9 Hz), 12.2(1H, br s).

IR(KBr) 3069, 1741, 1630, 1591, 1568, 1533, 1462, 1439, 1423, 1400,1305, 1238, 1170, 1155, 1130, 1101, 1066, 1030, 1010, 906, 756 cm⁻¹.

Elemental Analysis for C₁₇H₁₄N₂O₅S₂

Calcd. C, 52.30; H, 3.61; N, 7.17.

Found C, 52.16; H, 3.72; N, 6.98.

Example 347

2-(2-Methyl-1,3-thiazol-4-yl)-4H-1,3-benzothiazin-4-one

2-Methyl-1,3-thiazole-4-carbonitrile (0.46 g, 3.7 mmol) and methylthiosalicylate (1.26 g, 7.4 mmol) were dissolved in toluene (6 ml), andtriethylamine (3.0 ml, 21.5 mmol) was added thereto. The mixture wasrefluxed for 15 hrs. After cooling, the precipitates were collected byfiltration and recrystallized from ethanol to give the titled compound(0.75 g, 78%) as white crystals.

mp. 219.0-220.0° C.

¹H-NMR (CDCl₃) δ: 2.83 (3H, s), 7.55-7.70 (3H, m), 8.44 (1H, s), 8.55(1H, m).

IR(KBr): 3098, 1645, 1574, 1531, 1288, 1159, 740 cm⁻¹.

Elemental Analysis for C₁₂H₈N₂OS₂

Calcd. C, 55.36; H, 3.10; N, 10.76.

Found C, 55.53; H, 3.25; N, 10.71.

Example 348

2-(1,3-thiazol-2-yl)-4H-1,3-benzothiazin-4-one

1,3-Thiazole-2-carbonitrile (0.32 g, 2.9 mmol) and methyl thiosalicylate(0.98 g, 5.8 mmol) were dissolved in toluene (4 ml), and triethylamine(2.0 ml, 14.3 mmol) was added thereto. The reaction mixture was refluxedfor 2 hrs. After cooling, the precipitates were collected by filtrationand recrystallized from diisopropyl ether-ethanol to give the titledcompound (0.51 g, 70%) as yellow crystals.

mp. 229.1-229.8° C.

¹H-NMR (CDCl₃) δ: 7.60 (1H, m), 7.63 (1H, m), 7.68 (1H, m), 7.73 (1H,m), 8.10 (1H, m), 8.55 (1H, d, J=7.8 Hz).

IR(KBr): 3126, 1666, 1655, 1535, 1292, 866, 736 cm⁻¹.

Elemental Analysis for C₁₁H₆N₂OS₂

Calcd. C, 53.64; H, 2.46; N, 11.37.

Found C, 53.51; H, 2.35; N, 11.21.

Example 349

2-(4-Methyl-1,3-thiazol-2-yl)-4H-1,3-benzothiazin-4-one

4-Methyl-1,3-thiazole-2-carbonitrile (0.27 g, 2.2 mmol) and methylthiosalicylate (0.75 g, 4.4 mmol) were dissolved in toluene (4 ml), andtriethylamine (2.0 ml, 14.3 mmol) was added thereto. The reactionmixture was refluxed for 6 hrs. After cooling, the precipitates werecollected by filtration and recrystallized from ethanol to give thetitled compound (0.28 g, 49%) as yellow crystals.

mp. 209.6-210.7° C.

¹H-NMR (CDCl₃) δ: 2.58 (3H, s), 7.30 (1H, s), 7.56 (1H, d, J=7.6 Hz),7.60-7.71 (2H, m), 8.54 (1H, dd, J=0.7, 7.6 Hz).

IR(KBr): 3098, 1658, 1525, 1504, 1286, 738 cm⁻¹.

Elemental Analysis for C₁₂H₈N₂OS₂

Calcd. C, 55.39; H, 3.10; N, 10.76.

Found C, 55.23; H, 3.11; N, 10.55.

Example 350

2-[4-(1-Benzoyl-2-pyrrolidinyl)-2-pyridyl]-4H-1,3-benzothia zin-4-one

4-(1-Benzoyl-2-pyrrolidinyl)-2-pyridinecarbonitrile (0.42 g, 1.5 mmol)and methyl thiosalicylate (1.03 g, 6.1 mmol) were dissolved in toluene(4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. Themixture was refluxed for 14 hrs. The solvent was evaporated, and theresidue was subjected to a silica gel column chromatography. Thefractions eluted with ethyl acetate-hexane (4:1, v/v) were collected andconcentrated to give the titled compound (0.52 g, 82%) as amorphouscrystals.

¹H-NMR (CDCl₃) δ: 1.95-2.02 (3H, m), 2.40 (0.16H, m), 2.56 (0.83H, m),3.72 (0.83H, m), 3.83-3.91 (1H, m), 4.04 (0.16H, m), 5.01 (0.16H, m),5.32 (0.83H, m), 7.15 (0.83H, s), 7.30 (0.16H, s), 7.43-7.51 (3H, m),7.60-7.71 (5H, m), 8.14 (0.16H, m), 8.49 (0.83H, s), 8.55 (1H, d, J=8.0Hz), 8.67 (1H, d, J=4.8 Hz).

IR(KBr): 3057, 2974, 2876, 1658, 1631, 1572, 1537, 1408, 1294, 1095cm⁻¹.

Elemental Analysis for C₂₄H₁₉N₃O₂S·0.25H₂O

Calcd. C, 68.96; H, 4.70; N, 10.05.

Found C, 68.71; H, 4.79; N, 9.71.

Example 351

2-[4-(1-Acetyl-2-pyrrolidinyl)-2-pyridyl]-4H-1,3-benzothiaz ine-4-one

4-(1-Acetyl-2-pyrrolidinyl)-2-pyridinecarbonitrile (0.32 g, 1.5 mmol)and methyl thiosalicylate (1.02 g, 6.0 mmol) were dissolved in toluene(4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. Themixture was refluxed for 24 hrs. The solvent was evaporated, and theresidue was subjected to a silica gel column chromatography. Thefractions eluted with ethyl acetate-methanol (8:1, v/v) were collected,concentrated and recrystallized from diethyl ether-methanol to give thetitled compound (0.25 g, 48%) as white crystals.

mp. 206.2-207.4° C.

¹H-NMR (CDCl₃) δ: 1.64 (1H, s), 1.84-2.07 (3H, m), 2.17 (2H, s), 2.39(0.67H, m), 2.50 (0.33H, m), 3.67 (0.67H, m), 3.77-3.85 (1.33H, m), 5.03(0.33H, m), 5.18 (0.67H, m), 7.32-7.35 (1H, m), 7.60-7.71 (3H, m), 8.33(0.67H, s), 8.45 (0.33H, s), 8.53-8.56 (1H, m), 8.64 (0.67H, d, J=4.9Hz), 8.72 (0.33H, d, J=4.9 Hz).

IR(KBr): 3437, 2974, 2876, 1651, 1570, 1535, 1439, 1415, 1296, 1282,1095 cm⁻¹.

Elemental Analysis for C₁₉H₁₇N₃O₂S

Calcd. C, 64.94; H, 4.88; N, 11.96.

Found C, 64.64; H, 4.98; N, 11.81.

Example 352

tert-Butyl 2-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]-1-pyrrolidinecarboxylate

tert-Butyl 2-(2-cyano-4-pyridyl)-1-pyrrolidinecarboxylate (1.6 g, 6.0mmol) and methyl thiosalicylate (3.0 g, 18.3 mmol) were dissolved intoluene (10 ml), and triethylamine (5.0 ml, 35.8 mmol) was addedthereto. The mixture was refluxed for 18 hrs. The solvent wasevaporated, and the residue was subjected to a silica gel columnchromatography. The fractions eluted with ethyl acetate-hexane (1:1,v/v) were collected, concentrated and recrystallized fromhexane-tetrahydrofuran to give the titled compound (1.5 g, 63%) as whitecrystals.

mp. 194.8-195.8° C.

¹H-NMR (CDCl₃) δ: 1.19 (5.4H, s), 1.46 (3.6H, s), 1.80-1.96 (3H, m),2.41 (1H, m), 3.59 (0.4H, m), 3.67 (1.6H, m), 4.85 (0.6H, m), 4.96(0.4H, m), 7.36 (1H, m), 7.61-7.71 (3H, m), 8.40 (1H, s), 8.56 (1H, d,J=7.5 Hz), 8.65 (1H, d, J=4.6 Hz)

IR(KBr): 2974, 1693, 1666, 1537, 1392, 1165 cm⁻¹.

Elemental Analysis for C₂₂H₂₃N₃O₃S

Calcd. C, 64.53; H, 5.66; N, 10.26.

Found C, 64.48; H, 5.64; N, 10.13.

Example 353

2-[4-(2-Pyrrolidinyl)-2-pyridyl]-4H-1,3-benzothiazine-4-onetrifluoroacetic acid salt

tert-Butyl 2-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]-1-pyrrolidinecarboxylate (0.35 g, 0.85 mmol) was dissolved in trifluoroacetic acid(5 ml), and the mixture was stirred at room temperature for 3 hrs. Thesolvent was evaporated, and the residue was recrystallized fromdiisopropyl ether-methanol to give the titled compound (0.31 g, 85%) aswhite crystals.

mp. 187.5-189.0° C.

¹H-NMR (DMSO-d₆) δ: 1.97-2.21 (3H, m), 2.56 (1H, m), 3.33-3.50 (2H, m),4.80 (1H, m), 7.75 (1H, m), 7.83-7.88 (2H, m), 7.95 (1H, d, J=8.0 Hz),8.37 (1H, d, J=7.9 Hz), 8.52 (1H, s), 8.89 (1H, d, J=4.9 Hz), 9.48 (2H,br s).

IR(KBr): 2984, 2762, 1660, 1535, 1203, 1172, 1124, 827 cm⁻¹.

Elemental Analysis for C₁₉H₁₆N₃O₃SF₃

Calcd. C, 53.90; H, 3.81; N, 9.92.

Found C, 53.74; H, 3.91; N, 9.96.

Example 354

2-[4-(2-Pyrrolidinyl)-2-pyridyl]-4H-1,3-benzothiazine-4-onehydrochloride salt

tert-Butyl 2-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]-1-pyrrolidinecarboxylate (0.40 g, 0.97 mmol) was dissolved in ethyl acetate (25ml), and 4 N hydrogen chloride-ethyl acetate solution (8 ml) was addeddropwise thereto at room temperature. The mixture was stirred at thesame temperature for 30 minutes. The precipitates were collected byfiltration and recrystallized from diethyl ether-methanol to give thetitled compound (0.10 g, 31%) as white crystals.

mp. 219.4-221.4° C.

¹H-NMR (DMSO-d₆) δ: 2.00-2.15 (3H, m), 2.52 (1H, m), 3.34-3.47 (2H, m),4.77 (1H, m), 7.74 (1H, m), 7.86 (1H, m), 7.93-7.96 (2H, m), 8.38 (1H,m), 8.49 (1H, s), 8.88 (1H, d, J=5.0 Hz), 9.49 (1H, br s), 10.27 (1H, brs).

Elemental Analysis for C₁₇H₁₆N₃OSCl·0.25H₂O

Calcd. C, 58.28; H, 4.75; N, 11.99.

Found C, 58.18; H, 4.84; N, 11.94.

Example 355

tert-Butyl 3-[2-cyano-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate

tert-Butyl 3-(2,6-dicyano-4-pyridyl)propanoate (1.4 g, 5.5 mmol) andmethyl thiosalicylate (1.7 g, 10.1 mmol) were dissolved in toluene (10ml), and triethylamine (5.0 ml, 35.8 mmol) was added thereto. Themixture was refluxed for 3 hrs. The solvent was evaporated, and theresidue was subjected to a silica gel column chromatography. Thefractions eluted with ethyl acetate-hexane (2:3, v/v) were collected,concentrated and recrystallized from hexane-tetrahydrofuran to give thetitled compound (0.79 g, 36%) as white crystals.

mp. 189.9-190.7° C.

¹H-NMR (CDCl₃) δ: 1.43 (9H, s), 2.67 (2H, t, J=7.2 Hz), 3.08 (2H, t,J=7.2 Hz), 7.64-7.73 (3H, m), 7.79 (1H, d, J=1.4 Hz), 8.56 (1H, m), 8.61(1H, d, J=1.4 Hz).

IR(KBr): 2978, 2932, 1724, 1664, 1572, 1537, 1294, 1151 cm⁻¹.

Elemental Analysis for C₂₁H₁₉N₃O₃S

Calcd. C, 64.10; H, 4.87; N, 10.68.

Found C, 64.13; H, 5.10; N, 10.44.

Example 356

3-[2-Cyano-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]pro panoate

tert-Butyl 3-(2-cyano-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate (0.41 g, 1.05 mmol) was dissolved in trifluoroacetic acid (5ml), and the mixture was stirred at 0° C. for 2 hrs. The solvent wasevaporated, and the residue was recrystallized from methanol to give thetitled compound (0.27 g, 76%) as pale yellow crystals.

mp. 271.0-272.7° C.

¹H-NMR (DMSO-d₆) δ: 2.74 (2H, t, J=7.3 Hz), 3.06 (2H, t, J=7.3 Hz), 7.74(1H, m), 7.85 (1H, m), 7.97 (1H, d, J=8.0 Hz), 8.32 (1H, s), 8.35 (1H,d, J=7.9 Hz), 8.50 (1H, s), 12.29 (1H, br s).

IR(KBr): 3074, 1724, 1635, 1589, 1535, 1440, 1317, 1161, 887 cm⁻¹.

Elemental Analysis for C₁₇H₁₁N₃O₃S·0.25H₂O

Calcd. C, 59.73; H, 3.39; N, 12.29.

Found C, 59.82; H, 3.69; N, 11.97.

Experimental Example 1

Inhibitory Activity on Heart Muscle Cell Apoptosis

Newborn rats (within 1 day after birth) were obtained from pregnantWister rats purchased from Charles River, anesthetized under ether, andsterilized with 70% ethanol, and then their hearts were excised withtweezers. The excised hearts were washed with a phosphate-bufferedphysiological saline (T900; Takara) and cut into pieces with surgicalscissors. These tissue pieces were washed 4 to 5 times with aphosphate-buffered physiological saline to remove a majority ofblood-derived non-heart muscle cells. To the tissue pieces derived from10 newborns, 5 ml of enzyme solution (1.25 mg trypsin (Difco) and 0.25mg collagenase (Sigma) per ml of phosphate-buffered saline (PBS)) wasadded and the mixture was stirred with a stirrer at 37° C. for 15minutes. Another 2.5 ml enzyme solution was then added twice repeatedlyat a 15-minutes interval. Then, Medium 199 (Gibco) containing 10% fetalcalf serum (Biowiker) was added in a half volume of the enzyme solutionto terminate the enzyme reaction. The cells were filtered through a CellStrainer (Falcon) and then centrifuged at 400×g for 5 minutes, wherebythe cells were collected.

The cells thus collected from 10 newborns were suspended in 50 ml Medium199 containing 10% fetal calf serum, plated onto 100 mm Petri dishes(Iwaki) in a volume of 10 ml/dish and cultured for 1 hour in a CO₂incubator set at 5% CO₂ and 37° C. The cells were then recovered,filtered through a Cell Strainer and centrifuged at 400×g for 5 minutesto collect the primary heart muscle cells derived from newborn rats.

Then, the heart muscle cells from 10 newborn rats were suspended in 2 mllow-isotonic solution (prepared by dissolving 8.29 g NH₄Cl, 1.0 g KHCO₃,37 mg EDTA/2Na (ethylenediaminetetraacetic acid disodium) (Dojindo) in 1L of water) and left for 3 minutes to disrupt erythrocytes. After 10 mlMedium 199 containing 10% fetal calf serum was added thereto, theprimary heart muscle cells from newborn rats were collected bycentrifugation at 400×g for 5 minutes. The cells were suspended inMedium 199 containing 10% fetal calf serum and then filtered through acell strainer. After 0.3% trypan blue was added to, and mildly mixedwith, an aliquot of the resulting cell suspension, the number of heartmuscle cells was counted on an erythrocyte counting plate.

The primary heart muscle cells from newborn rats were suspended at adensity of 3×10⁶ cells/ml in Medium 199 containing 10% fetal calf serum,put onto a 96-well plate in a volume of 0.1 ml/well, and then culturedin a CO₂ incubator set at 5% CO₂ and 37° C. After the plate was stirredwith a micromixer (Taiyo Kagaku Kogyo), the medium was exchanged 3 timeswith serum-free Medium 199, and then test compounds (Compounds 1 to 5obtained in Reference Examples) were added thereto. The cells werecultured for additional 4 days to induce apoptosis. Then, fetal calfserum was added thereto at a concentration of 10%, and the cells werefurther cultured for about 17 hours in a CO₂ incubator set at 5% CO₂ and37° C. Finally, the number of viable cells was determined with CellCounting Kit (Dojindo) using WST-8(2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt) as the coloring substrate todetermine the inhibition of the heart muscle cell apoptosis.

The above-mentioned experiment was triplicated in an independent manner.

The Mean minimal effective concentration (±SD) was shown for each testcompound (Compounds 1 to 5 obtained in Reference Examples) in Table 1.In Table 1, the minimal effective concentration is defined as theconcentration required to increase the mean viable cell number by 50% ascompared with that in the absence of test compounds. TABLE 1 Ex.Compound No. Minimal Effective Concentration (μM) 7 0.021 10 0.023 190.025 20 0.038 21 0.030 28 0.025 29 0.035 30 0.012 37 0.037 38 0.013 390.037 40 0.044 43 0.053 47 0.017 48 0.043 49 0.043 50 0.020 51 0.034 520.010 53 0.032 54 0.037 55 0.016 56 0.039 57 0.033 58 0.091 60 0.019 610.010 63 0.046 64 0.052 65 0.045 67 0.031 68 0.018 70 0.017 73 0.024 750.035 76 0.036 77 0.039 79 0.061 80 0.035 81 0.012 82 0.011 83 0.027 850.040 99 0.043 100 0.036 102 0.036 103 0.042 104 0.019 105 0.028 1060.052 107 0.012 111 0.037 112 0.051 113 0.022 115 0.052 126 0.032 1270.040 128 0.081 133 0.06 134 0.095

This result shows that Example Compounds have the inhibitory activity onheart muscle cell apoptosis.

Formulation Example 1

Capsule (1) Compound obtained in Example 45 20 mg (2) lactose 60 mg (3)microcrystalline cellulose 9 mg (4) magnesium stearate 1 mg 1 capsule100 mg (1), (2), (3) and 1/2 of (4) were mixed and granulated. Theremained (4) was added thereto, and the whole of them is enclosed intogelatin capsules.

Formulation Example 2

(1) Compound obtained in Example 45 30 mg (2) lactose 48 mg (3) cornstarch 18 mg (3) microcrystalline cellulose 3.5 mg (5) magnesiumstearate 0.5 mg 1 tablet 100 mg (1), (2), (3), 2/3 of (4) and 1/2 of (5)were mixed and granulated. The remained (4) and (5) were added thereto,and they were compressed to form tablets.

INDUSTRIAL APPLICABILITY

This invention provides novel 1,3-benzothiazinone derivatives having anexcellent apoptosis inhibitory effect and MIF binding effect and thelike. They are safe and useful drugs for preventing and/or treatingheart disease, nervous degenerative disease, cerebrovascular disease,central nervous infectious disease, traumatorathy, demyelinatingdisease, bone and articular disease, kidney ischemia, liver disease,osteomyelodysplasia, AIDS, cancer, and the like.

1. A compound represented by the formula:

wherein R¹ is a hydrogen atom, a halogen atom, hydroxy, nitro,optionally halogenated alkyl, alkoxy optionally having substituents,acyl or amino optionally having substituents; R² is pyridyl, furyl,thienyl, pyrrolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl,indolyl, tetrahydroquinolyl or thiazolyl, each of which may havesubstituents; n is 1 or 2; or a salt.
 2. The compound according to claim1, wherein R² is pyridyl, furyl, thienyl, pyrrolyl, quinolyl, pyrazinyl,pyrimidinyl, pyridazinyl or indolyl, each of which may havesubstituents.
 3. The compound according to claim 1, wherein the compoundis represented by the formula:

wherein R^(1a) is a hydrogen atom, a halogen atom, optionallyhalogenated alkyl or optionally halogenated alkoxy; R² has the samemeaning as described in claim
 1. 4. The compound according to claim 1,wherein R¹ is a halogen atom, hydroxy, nitro, optionally halogenatedalkyl, alkoxy optionally having substituents, acyl or amino optionallyhaving substituents.
 5. The compound according to claim 1, wherein R¹ isa hydrogen atom.
 6. The compound according to claim 1, wherein the“pyridyl which may have substituents” is pyridyl which has substituents.7. The compound according to claim 1, wherein R¹ is a hydrogen atom; the“pyridyl which may have substituents” is pyridyl which has substituents.8. The compound according to claim 1, wherein R¹ is a halogen atom. 9.The compound according to claim 1, wherein R² is pyridyl which may havesubstituents.
 10. The compound according to claim 1, wherein R² ispyridyl which has substituents.
 11. The compound according to claim 1,wherein R² is 2- or 4-pyridyl which may have substituents.
 12. Thecompound according to claim 1, wherein R² is pyridyl, furyl, thienyl,pyrrolyl, quinolyl, pyrazinyl, pyrimidinyl, indolyl, tetrahydroquinolylor thiazolyl, each of which may have substituents;
 13. The compoundaccording to claim 1, wherein R² is pyridyl, furyl, thienyl, pyrrolyl,quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl,tetrahydroquinolyl or thiazolyl, each of which may have 1 to 3substituent(s) selected from the group consisting of (1) a halogen atom,(2) a C₁₋₆ alkyl which may have 1 to 5 substituent(s) selected from thegroup consisting of (i) a halogen atom, (ii) hydroxy, (iii) carboxy,(iv) cyano, (v) carboxy-C₁₋₆ alkoxy, (vi) C₁₋₆ alkoxy-C₁₋₆alkoxy, (vii)C₁₋₆alkoxy-carbonyl-C₁₋₆ alkoxy, (viii) C₁₋₆ alkyl-carbonyloxy, (ix)C₁₋₆ alkoxy-carbonyl, (x) carbamoyl which may have 1 or 2 substituent(s)selected from the group consisting of (a) mono- or di-C₁₋₆ alkyl whichmay have carboxy, (b) C₁₋₆ alkylsulfonyl and (c) C₆₋₁₀ arylsulfonyl,(xi) 5- or 6-membered saturated cyclic amino-carbonyl which may havecarboxy, (xii) C₁₋₆alkylthio which may have C₁₋₆alkoxy-carbonyl, (xiii)C₁₋₆ alkylsulfinyl which may have C₁₋₆ alkoxy-carbonyl, (xiv) C₁₋₆alkylsulfonyl which may have C₁₋₆ alkoxy-carbonyl, (xv) C₇₋₁₂aralkylthio, (xvi) C₇₋₁₂ aralkylsulfinyl, (xvii) C₇₋₁₂ aralkylsulfonyl,(xviii) (5- or 6-membered aromatic heterocycle)-thio, (xix) amino whichmay have 1 or 2 substituent(s) selected from the group consisting of (a)C₁₋₆ alkyl, (b) C₁₋₆alkoxy-carbonyl, (c) optionally halogenated C₁₋₆alkyl-carbonyl, (d) C₆₋₁₀ aryl-carbonyl, (e) thienylcarbonyl, (f) C₁₋₆alkylthio-C₁₋₆ alkyl-carbonyl, (g) mono- or di-C₁₋₆ alkyl-carbamoyl, (h)C₃₋₆ alkylsulfonyl, (i) C₆₋₁₀ arylsulfonyl, (j) di-C₁₋₆alkylphosphono,(k) di-C₁₋₆alkylthiophosphono and (1) C₆₋₁₀ aryl-carbamoyl, (xx)phthalimido, (xxi) C₁₋₆ alkylsulfonyloxy, (xxii) 5-or 6-memberedaromatic heterocyclic group, (xxiii) phosphono which may have C₁₋₆alkyl, (xxiv) 5- to 7-membered saturated cyclic amino which may have 1or 2 substituent(s) selected from the group consisting of (a) C₇₋₁₂aralkyl, (b) optionally halogenated C₆₋₁₀ aryl and (c) hydroxy and (xxv)(5- to 7-membered cyclic amino)-carbonyl, (3) C₁₋₆ alkenyl which mayhave carboxy or C₁₋₆ alkoxy-carbonyl, (4) C₆₋₁₀ aryl which may have C₁₋₆alkoxy, (5) C₁₋₆ alkoxy which may have substituents selected from thegroup consisting of C₁₋₆ alkoxy, C₁₋₆ alkoxy-carbonyl, phthalimido,di-C₁₋₆ alkylsulfonamido and di-C₁₋₆ alkylaminomethylenesulfonamido, (6)C₆₋₁₀ aryloxy which may have C₁₋₆ alkylthio, (7) C₇₋₁₂ aralkyloxy, (8)C₁₋₆ alkylthio which may have substituents selected from the groupconsisting of mono- or di-C₁₋₆ alkylamino, carboxy, carbamoyl and C₁₋₆alkoxy-carbonyl, (9) C₁₋₆ alkylsulfinyl which may have substituentsselected from the group consisting of mono- or di-C₁₋₆ alkylamino,carboxy, carbamoyl and C₁₋₆ alkoxy-carbonyl, (10) C₁₋₆ alkylsulfonylwhich may have substituents selected from the group consisting of mono-or di-C₁₋₆ alkylamino, carboxy and C₁₋₆ alkoxy-carbonyl, (11) C₆₋₁₀arylthio which may have substituents selected from the group consistingof halogen atom, C₁₋₆ alkyl and C₁₋₆ alkoxy-carbonyl, (12) C₆₋₁₀arylsulfinyl which may have C₁₋₆ alkyl, (13) C₆₋₁₀ arylsulfonyl whichmay have C₁₋₆ alkyl, (14) carboxy, (15) C₁₋₆ alkoxy-carbonyl, (16) C₇₋₁₂aralkylthio, (17) C₇₋₁₂ aralkylsulfinyl, (18) C₇₋₁₂ aralkylsulfonyl,(19) amino which may have 1 or 2 substituent(s) selected from the groupconsisting of C₁₋₆ alkyl, C₇₋₁₂ aralkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆alkoxy-carbonyl, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl, carboxy-C₁₋₆ alkyl,C₁₋₆ alkyl-carbonyl, C₆₋₁₀ aryl-carbonyl, C₃₋₆ cycloalkyl-carbonyl,thienylcarbonyl, furylcarbonyl and mono- or di-C₁₋₆ alkylamino-carbonyl,(20) 5- to 7-membered saturated cyclic amino which may have substituentsselected from the group consisting of (i) optionally halogenated C₆₋₁₀aryl, (ii) C₇₋₁₂ aralkyl, (iii) hydroxy, (iv) C₁₋₆ alkyl which may haveC₁₋₆ alkoxy-carbonyl or carboxy, (v) oxo, (vi) C₁₋₆ alkyl-carbonyl,(vii) C₆₋₁₀ aryl-carbonyl and (viii) C₁₋₆ alkoxy-carbonyl, (21)carbamoyl which may have substituents selected from the group consistingof (i) C₁₋₆ alkyl which may have substituents selected from the groupconsisting of halogen atom, C₁₋₆ alkoxy, amino, C₁₋₆ alkoxy-carboxamidoand hydroxy, (ii) C₇₋₁₂ aralkyl and (iii) mono- or di-C₁₋₆alkylamino-carbonyl, (22) (5- to 7-membered cyclic amino)-carbonyl, (23)5- or 6-membered aromatic heterocyclic group which may have C₁₋₆ alkyl,(24) cyano, (25) (5- to 10-membered aromatic heterocycle)-thio which mayhave C₁₋₆ alkyl, (26) C₁₋₆ alkylcarbonyl and (27) oxo.
 14. The compoundaccording to claim 1 or 3, wherein R² is optionally N-oxidized pyridylwhich may have 1 to 3 substituent(s) selected from the group consistingof (1) a halogen atom, (2) a C₁₋₆ alkyl which may have substituentsselected from the group consisting of a halogen atom, C₁₋₆alkyl-carbonyloxy, C₁₋₆ alkoxy-C₁₋₆ alkoxy, hydroxy, C₁₋₆alkoxy-carbonyl-C₁₋₆ alkoxy, carboxy-C₁₋₆alkoxy, carboxy, C₁₋₆alkoxy-carbonyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl,C₁₋₆ alkylsulfonyloxy, 5- or 6-membered saturated cyclic amino, C₁₋₆alkylsulfonyl-carbamoyl, C₆₋₁₀ arylsulfonyl-carbamoyl and (5- to7-membered cyclic amino)-carbonyl, (3) C₂₋₆ alkenyl which may havecarboxy or C₁₋₆ alkoxy-carbonyl, (4) C₆₋₁₀ aryl, (5) C₁₋₆ alkoxy whichmay have substituents selected from the group consisting of C₁₋₆alkoxy,C₁₋₆ alkoxy-carbonyl, phthalimido, di-C₁₋₆ alkylsulfonamido and di-C₁₋₆alkylaminomethylenesulfonamido, (6) C₆₋₁₀ aryloxy which may have C₃₋₆alkylthio, (7) C₇₋₁₂ aralkyloxy, (8) C₁₋₆ alkylthio which may have mono-or di-C₁₋₆ alkylamino or C₁₋₆ alkoxy-carbonyl, (9) C₁₋₆ alkylsulfinylwhich may have mono- or di-C₁₋₆alkylamino, (10) C₁₋₆ alkylsulfonyl whichmay have mono- or di-C₁₋₆alkylamino, (11) C₆₋₁₀ arylthio which may havesubstituents selected from the group consisting of halogen atom, C₁₋₆alkyl and C₁₋₆ alkoxy-carbonyl, (12) C₆₋₁₀ arylsulfinyl which may haveC₁₋₆ alkyl, (13) C₆₋₁₀ arylsulfonyl which may have C₁₋₆ alkyl, (14)carboxy, (15) C₁₋₆ alkoxy-carbonyl, (16) C₇₋₁₂ aralkylthio, (17) C₇₋₁₂aralkylsulfinyl, (18) C₇₋₁₂ aralkylsulfonyl, (19) amino which may havesubstituents selected from the group consisting of C₁₋₆ alkyl, C₇₋₁₂aralkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-carbonyl, C₁₋₆alkyl-carbonyl, C₆₋₁₀ aryl-carbonyl, C₃₋₆ cycloalkyl-carbonyl,thienylcarbonyl, furylcarbonyl and mono- or di-C₁₋₆ alkylamino-carbonyl,(20) 5- to 7-membered saturated cyclic amino which may have substituentsselected from the group consisting of optionally halogenated C₆₋₁₀ aryl,C₁₋₆alkyl-carbonyl, C₆₋₁₀ aryl-carbonyl and C₁₋₆ alkoxy-carbonyl, (21)carbamoyl which may have substituents selected from the group consistingof (i) C₁₋₆ alkyl which may have substituents selected from the groupconsisting of halogen atom, C₁₋₆ alkoxy, amino and C₁₋₆alkoxy-carboxamido, (ii) C₇₋₁₂ aralkyl and (iii) mono- or di-C₁₋₆alkylamino-carbonyl, (22) (5- to 7-membered cyclic amino)-carbonyl, (23)pyridyl, thienyl, furyl, pyrazolyl or oxazolyl, each of which may haveC₁₋₆ alkyl and (24) oxo.
 15. The compound according to claim 1, whereinR² is furyl, thienyl, pyrrolyl, quinolyl, pyrazinyl, pyrimidinyl,indolyl, tetrahydroquinolyl or thiazolyl, each of which may have 1 or 2substituent(s) selected from (1) C₁₋₆ alkyl, (2) amino which may have 1or 2 substituent(s) selected from the group consisting of C₁₋₆alkyl,C₁₋₆ alkoxy-carbonyl, C₁₋₆alkoxy-carbonyl-C₃₋₆ alkyl and carboxy-C₁₋₆alkyl, (3) C_(1.6) alkylsulfonyl and (4) mono- or di-C₁₋₆alkylamino-C₁₋₆ alkylthio.
 16. The compound according to claim 1,wherein R² is pyridyl which may have 1 or 2 substituent(s) selected fromthe group consisting of (1) C₁₋₆ alkyl which may have substituentsselected from the group consisting of C₃₋₆ alkoxy-carbonyl-C₁₋₆ alkoxy,carboxy-C₁₋₆ alkoxy, carboxy, C₁₋₆ alkoxy-carbonyl and C₁₋₆alkylsulfonyloxy, (2) C₂₋₆ alkenyl which may have carboxy or C₁₋₆alkoxy-carbonyl, (3) C₁₋₆ alkylthio which may have mono- or di-C₁₋₆alkylamino or C₁₋₆ alkoxy-carbonyl, (4) C₁₋₆alkylsulfinyl which may havemono- or di-C₁₋₆ alkylamino, (5) C₁₋₆ alkylsulfonyl which may have mono-or di-C₁₋₆ alkylamino, (6) C₇₋₁₂ aralkylthio, (7) C₇₋₁₂ aralkylsulfinyl,(8) C₇₋₁₂ aralkylsulfonyl, (9) carbamoyl which may have substituentsselected from the group consisting of (i) C₁₋₆ alkyl which may havesubstituents selected from the group consisting of halogen atom, C₁₋₆alkoxy and amino, (ii) C₇₋₁₂ aralkyl and (iii) mono- or di-C₁₋₆alkylamino-carbonyl and (10) (5- to 7-membered cyclic amino)-carbonyl.17. The compound according to claim 1, wherein R (1) a hydrogen atom,(2) a halogen atom, (3) hydroxy, (4) optionally halogenated C₁₋₆ alkyl,(5) C₁₋₆ alkoxy which may have substituents selected from the groupconsisting of carboxy, hydroxy, C₁₋₆ alkoxy-carbonyl and C₆₋₁₀ aryl, (6)C₁₋₆ alkyl-carbamoyl, (7) C₃₋₆ cycloalkyl-carbamoyl, (8) (5- or6-membered saturated cyclic amino)-carbonyl or (9) carboxy.
 18. Thecompound according to claim 16, wherein R¹ is a hydrogen atom or ahalogen atom.
 19. The compound according to claim 1, wherein R¹ is ahalogen atom or a hydrogen atom, R² is pyridyl which may have 1 or 2substituent(s) selected from the group consisting of C₁₋₆ alkyl,carboxy-C₁₋₆ alkyl and C₁₋₆ alkylsulfonyl. 20.3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propionic acid,3-[6-(7-chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-4-methyl-2-pyridyl]propionic acid,3-[2-(7-chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]pr opionicacid, 3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propionic acid,3-[2-methyl-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]pr opionicacid, 3-[2-(7-chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-6-methyl-4-pyridyl]propionic acid or salts thereof.
 21. The compound according toclaim 1, which has an ability to bind macrophage migration-inhibitoryfactor.
 22. A pharmaceutical, which comprises a compound according toclaim 1, a salt thereof or prodrug thereof.
 23. The pharmaceuticalaccording to claim 22, which is a pharmaceutical for inhibition ofapoptosis or protection of cells.
 24. The pharmaceutical according toclaim 22, which is a pharmaceutical for inhibition of apoptosis.
 25. Thepharmaceutical according to claim 23, which is a pharmaceutical forinhibition of heart muscle cells apoptosis.
 26. The pharmaceuticalaccording to claim 22, which is a pharmaceutical for preventing and/ortreating apoptosis derived diseases.
 27. The pharmaceutical according toclaim 22, which is a pharmaceutical for preventing and/or treatingmacrophage migration-inhibitory factor derived diseases.
 28. Thepharmaceutical according to claim 22, which is a pharmaceutical forpreventing and/or treating circulatory disease, bone and articulardisease, infectious disease, inflammatory bowel disease or kidneydisease.
 29. A method for preventing and/or treating circulatorydisease, bone and articular disease, infectious disease, inflammatorybowel disease or kidney disease, which comprises administering aneffective amount of the compound according to claim 1, a salt thereof ora prodrug thereof to a mammal.
 30. Use of the compound according toclaim 1, a salt thereof or a prodrug thereof for producing apharmaceutical for preventing and/or treating circulatory disease, boneand articular disease, infectious disease, inflammatory bowel disease orkidney disease.